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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Parallel artificial membrane permeability assay (PAMPA) is a screening tool for the evaluation of drug permeability across various biological membrane system..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Parallel artificial membrane permeability assay (PAMPA) is a screening tool for the evaluation of drug permeability across various biological membrane system..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="Drug Discovery,Permeability,fluorescence,cucurbituril,Passive diffusion"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.597927/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="8"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Chemistry"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Chem."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="2296-2646"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fchem.2020.597927"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="597927"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="Drug Discovery; Permeability; fluorescence; cucurbituril; Passive diffusion"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Parallel artificial membrane permeability assay (PAMPA) is a screening tool for the evaluation of drug permeability across various biological membrane systems in a microplate format. In PAMPA, a drug candidate is allowed to pass through the lipid layer of a particular well during an incubation period of, typically, 10–16 h. In a second step, the samples of each well are transferred to a UV-Vis–compatible microplate and optically measured (applicable only to analytes with sufficient absorbance) or sampled by mass-spectrometric analysis. The required incubation period, sample transfer, and detection methods jointly limit the scalability of PAMPA to high-throughput screening format. We introduce a modification of the PAMPA method that allows direct fluorescence detection, without sample transfer, in real time (RT-PAMPA). The method employs the use of a fluorescent artificial receptor (FAR), composed of a macrocycle in combination with an encapsulated fluorescent dye, administered in the acceptor chamber of conventional PAMPA microplates. Because the detection principle relies on the molecular recognition of an analyte by the receptor and the associated fluorescence response, concentration changes of any analyte that binds to the receptor can be monitored (molecules with aromatic residues in the present example), regardless of the spectroscopic properties of the analyte itself. Moreover, because the fluorescence of the (upper) acceptor well can be read out directly by fluorescence in a microplate reader, the permeation of the drug through the planar lipid layer can be monitored in real time. Compared with the traditional assay, RT-PAMPA allows not only quantification of the permeability characteristics but also rapid differentiation between fast and slow diffusion events.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.597927/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2020/10/06"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2020/11/03"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="He, Suhang"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Department of Life Sciences and Chemistry, Jacobs University Bremen, Germany"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Zhiti, Anxhela"><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Department of Life Sciences and Chemistry, Jacobs University Bremen, Germany"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Barba-Bon, Andrea"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="Department of Life Sciences and Chemistry, Jacobs University Bremen, Germany"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Hennig, Andreas"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="Department of Life Sciences and Chemistry, Jacobs University Bremen, Germany"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Nau, Werner M."><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Department of Life Sciences and Chemistry, Jacobs University Bremen, Germany"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fchem.2020.597927"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.597927/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":2.924993,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"172952b2292dc247"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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Chem.</span> <span>, 03 November 2020</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Supramolecular Chemistry </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 8 - 2020 | </span> <a href="https://doi.org/10.3389/fchem.2020.597927" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fchem.2020.597927 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Supramolecular Ensembles Modified by Small Organic Molecules for Biosensing and Therapy</span> <span class="Link__wrapper"><a aria-label="View all 6 articles" href="https://www.frontiersin.org/research-topics/12704/supramolecular-ensembles-modified-by-small-organic-molecules-for-biosensing-and-therapy/articles" target="_self" data-event="customLink-link-a_viewAll6Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 6 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper notranslate"> <a href="https://loop.frontiersin.org/people/948913" class="user-id-948913"><img class="pr5" src="https://loop.frontiersin.org/images/profile/948913/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="\nSuhang He
">Suhang He</a><sup>*</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Anxhela Zhiti" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Anxhela Zhiti</span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1120234" class="user-id-1120234"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1120234/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Andrea Barba-Bon">Andrea Barba-Bon</a></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/921762" class="user-id-921762"><img class="pr5" src="https://loop.frontiersin.org/images/profile/921762/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Andreas Hennig">Andreas Hennig</a></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/500593" class="user-id-500593"><img class="pr5" src="https://loop.frontiersin.org/images/profile/500593/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Werner M. Nau
">Werner M. Nau</a><sup>*</sup></span></div> <ul class="notes"><li class="pl0">Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany</li> </ul> <p>Parallel artificial membrane permeability assay (PAMPA) is a screening tool for the evaluation of drug permeability across various biological membrane systems in a microplate format. In PAMPA, a drug candidate is allowed to pass through the lipid layer of a particular well during an incubation period of, typically, 10–16 h. In a second step, the samples of each well are transferred to a UV-Vis–compatible microplate and optically measured (applicable only to analytes with sufficient absorbance) or sampled by mass-spectrometric analysis. The required incubation period, sample transfer, and detection methods jointly limit the scalability of PAMPA to high-throughput screening format. We introduce a modification of the PAMPA method that allows direct fluorescence detection, without sample transfer, in real time (RT-PAMPA). The method employs the use of a fluorescent artificial receptor (FAR), composed of a macrocycle in combination with an encapsulated fluorescent dye, administered in the acceptor chamber of conventional PAMPA microplates. Because the detection principle relies on the molecular recognition of an analyte by the receptor and the associated fluorescence response, concentration changes of any analyte that binds to the receptor can be monitored (molecules with aromatic residues in the present example), regardless of the spectroscopic properties of the analyte itself. Moreover, because the fluorescence of the (upper) acceptor well can be read out directly by fluorescence in a microplate reader, the permeation of the drug through the planar lipid layer can be monitored in real time. Compared with the traditional assay, RT-PAMPA allows not only quantification of the permeability characteristics but also rapid differentiation between fast and slow diffusion events.</p> <div class="clear"></div> </div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb0">Drug absorption is a key factor in the evaluation of potential active pharmaceutical ingredients at the early stage of drug development. For orally administered drugs, the solubility and permeability in the gastrointestinal system determine whether the drug concentration can reach a sufficient therapeutic physiological level. The permeability of a drug is commonly estimated with empirical physicochemical chemometric methods (e.g., QSAR models) (<a href="#B22">Hou et al., 2004</a>), cell-based assays (Caco-2 assay) (<a href="#B2">Artursson et al., 2001</a>), or artificial membrane–based assays [e.g., parallel artificial membrane permeability assay (PAMPA)] (<a href="#B23">Kansy et al., 1998</a>; <a href="#B11">Faller, 2008</a>). While the cellular Caco-2 model is a highly informative screening model, there are limitations such as long differentiation period, poor interlaboratory reproducibility, and economic considerations (<a href="#B21">Hayeshi et al., 2008</a>). PAMPA has been introduced 20 years ago as a complementary tool to evaluate the passive transportation of drugs; the assay is conducted with specially designed and commercially available “sandwich-type” multiwell microplates, which consist of an acceptor plate and a donor plate that are separated by a lipid-infused microporous filter (<a href="#S1">Scheme 1A</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">SCHEME 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" name="scheme1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g004.jpg" alt="www.frontiersin.org" id="S1" loading="lazy"> </picture> </a> <p><strong>Scheme 1. (A)</strong> Working principle of RT-PAMPA and <strong>(B)</strong> schematic representation, as well as chemical structures of CB8, MDAP (as <math><msubsup><mrow><mtext>PF</mtext></mrow><mrow><mn>6</mn></mrow><mrow><mo>-</mo></mrow></msubsup></math> salt), the MDAP∙CB8 complex, as well as the MDAP∙CB8∙analyte ternary complex.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb15 w100pc float_left mt15">PAMPA has been used in combination with, or as an alternative to the Caco-2 assay, to improve efficiency and reproducibility (<a href="#B7">Berben et al., 2018</a>). Variables in PAMPA have been extensively studied, including the effect of stirring of the lower water layer, pH, and sink conditions. The thickness of the unstirred water layer, for example, is a critical parameter, especially for large drug molecules; in some circumstances, it can be a rate-limiting step (<a href="#B33">Wohnsland and Faller, 2001</a>; <a href="#B27">Nielsen and Avdeef, 2004</a>). The pH of the drug solution is another important factor, as the neutral form of a compound regularly has a larger permeability than the ionic one (<a href="#B29">Oja and Maran, 2015</a>). Besides, the <i>in vivo</i> absorptive sink condition (e.g., a pH gradient at the two sides of the membrane, blood flow, and serum proteins) has also been considered, which led to the development of the double-sink PAMPA method, as a variant (<a href="#B4">Avdeef, 2003</a>; <a href="#B5">Avdeef et al., 2004</a>). Because of its implementation as a single-point assay, the permeability value with PAMPA is obtained after a specific incubation time, typically 10–16 h (<a href="#B32">Sugano et al., 2001</a>). At this end point, the permeation process is interrupted by separating the acceptor from the donor plate and the samples of the individual wells are transferred to microplates suitable for UV-Vis quantification; for drug candidates with insufficient UV-Vis absorption, liquid chromatography–mass spectrometry (LC/MS) techniques are required for quantitative analysis, adding instrumental–analytical work for each and every well of analyte (<a href="#B20">Hanlan et al., 2003</a>).</p> <p class="mb15">In this experimental study, we administer a fluorescent artificial receptor (FAR) into the acceptor well of PAMPA (<a href="#S1">Scheme 1A</a>). The FAR is known to rapidly complex selected analytes by molecular recognition and thereby changes its fluorescence, either quenching or enhancement. Therefore, when the analyte is administered to the donor well of the PAMPA setup, its permeation through the artificial membrane connecting the acceptor and the donor plate can be followed in real time through a fluorescence intensity change, resulting in the setup of a real-time PAMPA (RT-PAMPA). From a chemical point of view, FARs are composed of a supramolecular reporter pair, that is, a macrocyclic host and a corresponding fluorescent dye molecule. Examples of commonly used FARs are 2,7-dimethyldiazapyrenium (MDAP) in combination with cucurbit[8]uril (CB8) (<a href="#B30">Sindelar et al., 2005</a>), berberine in a pair with cucurbit[7]uril (<a href="#B25">Megyesi et al., 2008</a>), and lucigenin together with <i>p</i>-sulfonato-calix[4]arene (<a href="#B18">Guo et al., 2011</a>). The sensing capabilities of these artificial receptors have already been demonstrated in the context of analyte transport through membrane porins (<a href="#B15">Ghale et al., 2014</a>; <a href="#B3">Assaf et al., 2019</a>; <a href="#B6">Barba-Bon et al., 2019</a>), for binding constant measurements (<a href="#B13">Florea and Nau, 2011</a>), for enzymatic reaction monitoring (<a href="#B17">Ghale et al., 2011</a>), and to demonstrate analyte uptake into cells (<a href="#B28">Norouzy et al., 2015</a>). The different FARs can be further classified according to their operational principle (competitive and associative binding mechanism) (<a href="#B31">Sinn and Biedermann, 2018</a>) or their phenomenological fluorescence intensity response upon analyte binding (“switch-on” vs. “switch-off”) (<a href="#B12">Florea et al., 2012</a>; <a href="#B16">Ghale and Nau, 2014</a>; <a href="#B9">Biedermann et al., 2015</a>). Among those, the first one, MDAP∙CB8, emerged as the most broadly applicable one (see chemical structures in <a href="#S1">Scheme 1B</a>), because it responds to a wide range of analytes with aromatic residues, which covers also numerous drugs and biomolecules of interest. The MDAP∙CB8 receptor operates through an associative mechanism (formation of a ternary complexes with the analyte, <a href="#S1">Scheme 1B</a>), and it displays a switch-off fluorescence response, due to intracavity quenching of the dye in the ternary complex. It is noteworthy that our present technical implementation draws inspiration from a recent assay method (FAR membrane assays), which has originally been developed for liposomal solutions to monitor analyte permeation through the vesicular membranes (<a href="#B8">Biedermann et al., 2020</a>).</p> <p class="mb0">To simplify the methodology in our present proof-of-concept study, the traditional PAMPA setup was employed, that is, without considering the unstirred water layers and sink conditions. As an important technical simplification of RT-PAMPA, the permeation process can be directly followed by measuring the fluorescence in the (upper) acceptor well in the microplate reader throughout the incubation period, that is, without the need to disassemble the plates as is common in the original UV-Vis and LC/MS implementations. Accordingly, the RT-PAMPA method differs not only chemically, because of the utilization of FARs, but also operationally, because of the direct fluorescence read-out. The latter is especially helpful when dealing with fast permeating drugs, as the lag time until the first read-out can be significantly reduced. It is also possible, as an additional perspective, to extract mechanistically relevant information, because the actual permeation kinetics can be measured, e.g., to assess saturation or lag effects or to differentiate monoexponential from multiexponential kinetic profiles. We found that the resulting RT-PAMPA, employing MDAP∙CB8 as FAR, responds very sensitively to electron-rich aromatic structures, such as indole. The methodology has been validated with different lipid solutions, e.g., 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine (DOPC), and cosolvents, and was shown to work robustly under various test conditions.</p> <a id="h3" name="h3"></a><h2>Materials and Methods</h2> <p class="mb0">CB8 was purchased from Strem Chemicals; the content was determined by <sup>1</sup>H NMR integration. MDAP and cucurbit[7]uril were synthesized according to the literature methods (<a href="#B24">Márquez et al., 2004</a>; <a href="#B10">Cejas and Raymo, 2005</a>). Berberine was purchased from Sigma–Aldrich and used without further purification. DOPC was purchased from TCI and used as received. Avanti PAMPA lipid blend I was purchased from Sigma; the lipid blend was a combination of DOPC and stearic acid at a ratio of 80:20 (wt/wt) and dissolved in dodecane with 1% ethanol. Analytes were purchased from Sigma–Aldrich or TCI and used without further purification. The 96-well Multiscreen IP filter plates (MAIPNTR10) were purchased from Merck Millipore, which are based on hydrophobic polyvinylidene fluoride as filter material. The donor plate was taken from the Corning Gentest precoated PAMPA system. For the screening experiments, 96-well black polystyrene microplates from Corning were used.</p> <h3>Parallel Artificial Membrane Permeability Assay</h3> <p class="mb0">Analyte solutions were prepared at 1 mmol/L in Millipore water or cosolvents as indicated. The MDAP∙CB8 reporter pair solution contained 5 μmol/L of MDAP and 6 μmol/L of CB8 that were dissolved in Millipore water. Two lipid solutions were used, including the commercial Avanti PAMPA lipid blend I and the self-prepared 2% DOPC in dodecane. To proceed with the assay, 5 μL of the lipid solution was pipetted to the microporous filter and allowed to impregnate evenly; 300 μL of the analyte solution was transferred to the lower donor well, and 100 μL of the reporter pair solution was transferred to the upper acceptor well. The acceptor plate was combined with the donor plate after the solutions had been loaded to define the start point of the assay. Fluorescence readings were taken on a Jasco FP-8500 fluorimeter equipped with a microplate reader with an excitation wavelength at 418 nm and monitored at an emission wavelength of 449 nm.</p> <h3>Screening Test</h3> <p class="mb0">Analyte screening and solvent effect studies were carried out in 96-well microplates; 150 μL of the reporter pair solution was pipetted into each well, followed by the addition of 15 μL of the analyte solution or solvent. For analytes that were insufficiently water-soluble but that dissolved with organic cosolvents, the final organic content was 2% after mixing with the reporter pair solution. Fluorescence was measured with the same parameters as for PAMPA. Intensity changes upon addition of the analyte solutions were recorded, and solvent-induced changes (background) were subtracted.</p> <a id="h4" name="h4"></a><h2>Results and Discussion</h2> <h3 class="pt0">Analyte Screening</h3> <p class="mb0">A recent report on the permeation of analytes across liposomal membranes tested MDAP∙CB8 and other fluorescent complexes as reporter pairs, providing us valuable information on the potential analytes that could be first implemented in the RT-PAMPA format (<a href="#B8">Biedermann et al., 2020</a>). To establish RT-PAMPA, we started with a small-scale analyte screening procedure, in order to eliminate false-negative results caused by the lack of response to the artificial receptor. These experiments could be performed in homogeneous solution, because only the fluorescence response of the receptor toward the analyte is being determined. A set of 29 analytes prepared in aqueous solution or with organic cosolvents has been examined for their response toward MDAP∙CB8. The fluorescence intensity changes upon addition of the analytes are visualized in <a href="#F1">Figure 1</a>. Most analytes caused a significant decrease of the fluorescence intensity, and changes >10% were considered to be sufficiently strong to be readily followed by RT-PAMPA, where a lower sensitivity was expected because of the temporal requirement of permeation. Indeed, the concentrations of the analytes in the fluorescence response experiments were conservatively set as 0.1 mmol/L, below the test concentrations used in the subsequent RT-PAMPA (1 mmol/L), such that already the permeation of a fraction of analyte from the donor to the acceptor well should ensure a fluorescence response in the upper.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1</strong>. Screening of the fluorescence response of the MDAP∙CB8 receptor upon addition of different analytes dissolved in water, 2% ethanol, and 2% DMSO, from top to bottom panels. The relative fluorescence intensity decrease upon addition of 20 equiv. of the corresponding analyte to 5 μmol/L MDAP∙CB8 reporter pair solution is shown.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb0 w100pc float_left mt15">The compounds that caused the largest fluorescence changes have several common structural features. MDAP possesses a positively charged conjugated organic moiety, which is predestined to get engaged in electrostatic interactions with electron-rich structures (e.g., indoles and coumarins). On the other hand, because of the size selectivity of the CB8 cavity with MDAP inside, large molecules and those with large branched residues showed no or weak associative binding (e.g., quinine, furosemide, primaquine, zolmitriptan, 1-adamantylamine, and 1-adamantanol). In general, an electron-rich, conjugated linear structure is preferred by the selected reporter pair. Naturally, because the sensing in RT-PAMPA is based on a molecular recognition process with an associated selectivity, the range of accessible analytes for a particular FAR is limited. Conversely, the technique is not limited to a single receptor. For example, berberine in combination with cucurbit[7]uril and lucigenin in a pair with <i>p</i>-sulfonato-calix[4]arene are alternative reporter pairs, which respond to different classes of analytes, e.g., adamantyl and polycyclic aliphatic derivatives for the former (<a href="#B25">Megyesi et al., 2008</a>; <a href="#B26">Moghaddam et al., 2011</a>) and compounds with tethered trimethylammonium groups for the latter (<a href="#B1">Arena et al., 2004</a>; <a href="#B19">Guo et al., 2008</a>, <a href="#B18">2011</a>). Through a combination of different receptors, the potential of RT-PAMPA can be expanded, although we concentrate herein on the demonstration for a single one, MDAP∙CB8.</p> <h3>Influence of Cosolvent</h3> <p class="mb15">Buffers and organic cosolvents are widely used in traditional PAMPA to increase drug solubility in water. Pharmaceutical libraries routinely involve compound storage in dimethyl sulfoxide (DMSO), and compatibility with this cosolvent always needs to be ensured. Accordingly, we examined the influence of organic cosolvents, including water mixtures with DMSO, methanol, and ethanol. These control experiments were important, because the molecular-recognition process with synthetic macrocyclic cavities, such as that in CB8 or the MDAP∙CB8 complex, is frequently driven by hydrophobic interactions, which are being modulated in different solvents.</p> <p class="mb0">The final concentration of the organic proportion ranged from 1 to 10% upon direct addition into the reporter pair solutions. As expected from a leveling of the hydrophobic driving force for receptor–analyte (host–guest) complexation in organic solvents, the fluorescence intensity decreased in all cases, and the effect became significant as the organic proportion increased (<a href="#F2">Figure 2</a>), with the largest drop (by 29%) being observed for 10% DMSO content. However, the response of the FAR was quite stable at low organic solvent proportion (1%), with the fluorescence intensity being reduced by only 5, 3, and 6% with methanol, ethanol, and DMSO, respectively. Although the results suggested that high proportions of organic cosolvent needed to be avoided, because they would reduce the sensitivity of the assay, the RT-PAMPA application should be sufficiently robust to allow common low DMSO proportions, and most importantly, the effect of organic cosolvents on the fluorescence response of the receptor was found to be predicable and systematic.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" name="figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a> <p><strong>Figure 2</strong>. Fluorescence intensity change of the MDAP∙CB8 reporter pair solution upon addition of methanol, ethanol, or DMSO to the desired final concentration.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Influence of Lipid Layer</h3> <p class="mb0">In PAMPA, a lipid barrier needs to be crossed when an analyte moves from the donor plate into the acceptor plate. The initial PAMPA used egg lecithin as the lipid bilayer membrane (<a href="#B23">Kansy et al., 1998</a>; <a href="#B11">Faller, 2008</a>); other options such as hexadecane (<a href="#B33">Wohnsland and Faller, 2001</a>) and lipid mixtures (<a href="#B32">Sugano et al., 2001</a>) have been developed subsequently. Herein, we selected a commercial Avanti lipid solution with good fluidity in all PAMPA experiments. As an alternative common lipid, 2% DOPC in dodecane solution has been used for comparison. Before proceeding to the RT-PAMPA experiments, we monitored the stability of the FAR in the acceptor well when in contact with the donor well in the absence of added analyte. Over a period of 7-h incubation time, a slight decrease of the fluorescence was monitored, which amounted to ca. 5 ± 2% for the 2% DOPC lipid and to 12 ± 3% for the Avanti premixed lipid (see <a href="#SM1">Supplementary Material</a>). Presumably, this decrease reflects some dissolution of the receptor, or a component of it, in the lipid layer. Interestingly, this drop was independent, within error, of the presence of organic cosolvent (up to 20%) in the donor layer, which demonstrates that the diffusion of the polar organic cosolvents through the lipid does not contribute to the fluorescence changes in this time scale.</p> <h3>RT-PAMPA</h3> <p class="mb0">In the actual RT-PAMPA experiments with MDAP∙CB8 and the Avanti lipid (<a href="#F3">Figure 3A</a>), the fluorescence decrease recorded from the different analytes needs to be compared with the fluorescence response in the absence of analyte, where also a slight decrease is observed (see previous section). Accordingly, significant fluorescence responses, indicative of analyte permeation through the lipid layer, were observed for umbelliferone, lansoprazole, <small>L</small>-tryptophanamide, coumarin, propanil, thiabendazole, and indole. <small>L</small>-Phenylalanine, serotonin, doxepin, and zolmitriptan showed no significant fluorescence response in comparison to the absence of analyte. Because these analytes show a strong fluorescence response in homogeneous solution (<a href="#F1">Figure 1</a>), they do not or too slowly permeate through the lipid layer in RT-PAMPA.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 3</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" name="figure3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/597927/fchem-08-597927-HTML/image_m/fchem-08-597927-g003.jpg" alt="www.frontiersin.org" id="F3" loading="lazy"> </picture> </a> <p><strong>Figure 3</strong>. RT-PAMPA with the MDAP∙CB8 fluorescent receptor and Avanti lipid films for monitoring the permeation process of <strong>(A)</strong> selected analytes that show binding to the fluorescent receptor and <strong>(B)</strong> indole at different analyte concentrations.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb15 w100pc float_left mt15">For compounds that show insignificant fluorescence response/binding toward the MDAP∙CB8 reporter pair, such as 1-adamantylamine or 1-adamantanol (<a href="#F1">Figure 1</a>), other reporter pairs can be in principle employed. To demonstrate, we conducted exploratory experiments (see <a href="#SM1">Supplementary Material</a>) with the berberine∙cucurbit[7]uril reporter pair, which showed a strong fluorescence response, indicative of effective permeation, toward 1-adamantylamine and 1-adamantanol. The variability of the reporter pairs presents an additional asset of RT-PAMPA, which at the same time limits its general applicability for screening larger libraries with a single reporter pair. Among the tested reporter pairs, MDAP∙CB8 was, however, found to surpass the other candidates in terms of accessible analyte scope.</p> <p class="mb15">The RT-PAMPA was carried out with two kinds of lipid membranes, the commercial Avanti PAMPA blend I and the laboratory prepared 2% DOPC dodecane solution (see <a href="#SM1">Supplementary Material</a> for all results with 2% DOPC). A better resolution between the different analytes was observed with the commercial lipid layer, possibly because it is more permeable by dissolving 1% ethanol and stearic acid in dodecane besides just DOPC. The comparison also afforded differences in permeation profiles of some analytes. For example, umbelliferone, which showed an appreciable permeability through the Avanti lipid (<a href="#F3">Figure 3A</a>), did not permeate to a significant extent through the 2% DOPC lipid under RT-PAMPA conditions. As a particular advantage of RT-PAMPA, fast and slow permeation characteristics can be immediately differentiated from the permeation curves. Fast permeation is reflected by a sharp drop of the fluorescence during the initial several minutes, e.g., for coumarin, propanil, thiabendazole, and indole, revealing that a significant amount of the analyte has rapidly crossed the membrane model. In contrast, slowly permeating compounds such as umbelliferone, lansoprazole, and <small>L</small>-tryptophanamide showed a fluorescence response on the time scale of several hours in RT-PAMPA. As expected, the kinetics of the permeation profiles (slow, moderate, and fast) nicely correlated with the known permeabilities of the analytes. For instance, the permeability coefficients (log<i>P</i><sub>e</sub>) of indole and coumarin are reported as −4.50 and −4.55, respectively, which are considered fast (<a href="#B14">Fujikawa et al., 2007</a>). In contrast, doxepin, whose permeability coefficient is < −6 in acidic solutions (which matches our experimental condition for using doxepin hydrochloride in the donor well), is categorized as slow permeation (<a href="#B29">Oja and Maran, 2015</a>). Meanwhile, the performance of <small>L</small>-tryptophanamide is moderate to slow with a permeability coefficient of −5.56 (<a href="#B14">Fujikawa et al., 2007</a>). It should also be noted that simple (single-parameter) empirical correlations between the permeability coefficients and other physicochemical parameters of the analytes (such as their molecular size or their lipophilicity as assessed by octanol–water partition coefficients) do not apply, which emphasizes the need to experimentally determine the permeabilities of analytes with dedicated assays, such as RT-PAMPA (<a href="#B14">Fujikawa et al., 2007</a>; <a href="#B8">Biedermann et al., 2020</a>).</p> <p class="mb0">RT-PAMPA is in principle also suitable to extract absolute permeation coefficients and rates, although these are strongly dependent on the actual experimental conditions (see above) and can only serve as a relative comparison and/or rough method-to-method comparison. The quantitative analysis requires that a plateau value for the final fluorescence intensity has been reached, which is indicative of analyte diffusion having reached equilibrium and/or complete consumption of the reporter pair. To differentiate between the two options, experiments at different analyte concentrations can be performed. For indole, see <a href="#F3">Figure 3B</a>; these experiments (from 0.01 to 1 mmol/L) revealed variations of the plateau with varying indole concentration, which signifies that the diffusion equilibrium is actually being attained and that the artificial receptor is not being consumed; in the latter case, the same plateau would be reached with different rates. Under those conditions of equilibration and with the knowledge of the binding affinity between the analyte and the reporter pair, the absolute permeability coefficients of the analyte can be extracted (see <a href="#SM1">Supplementary Material</a>). The effective permeability coefficient of indole (log <i>P</i><sub>e</sub>) was calculated as −4.57 (as an average value), which compares favorably with that reported by others (log <i>P</i><sub>e</sub> = −4.50, with 10% egg lecithin solution as the lipid barrier) (<a href="#B14">Fujikawa et al., 2007</a>). A closer inspection of the permeability coefficients calculated for different time intervals or for different indole concentrations (see <a href="#SM1">Supplementary Material</a>) shows small systematic trends (smaller values at higher analyte concentrations), which may be related to the almost complete consumption of the receptor at higher analyte concentrations and an associated larger error. Important to note, the presence of organic cosolvents in the donor well had a minor influence on the absolute permeation kinetics. To provide a specific example, we prepared 0.1 mmol/L thiabendazole samples in both 2 and 20% ethanol, and the resulting permeation curves overlapped within the time of largest changes (initial hour, see <a href="#SM1">Supplementary Material</a>).</p> <a id="h5" name="h5"></a><h2>Conclusions</h2> <p class="mb0">In summary, we have developed a real-time PAMPA model, referred to as RT-PAMPA, by introducing the FAR MDAP∙CB8 into the acceptor well. In contrast to the traditional single-point PAMPA, RT-PAMPA can offer multiple data point data along the entire incubation period, and it bypasses multiple incubation steps related to detection by UV-Vis absorption or measurement with LC/MS. A rational protocol to perform the RT-PAMPA involves analyte screening as a preliminary test to evaluate the response of the fluorescent receptor to the analyte. For analytes that interact with the reporter pair, the complexation-induced fluorescence change in RT-PAMPA can be recorded in real time along during analyte incubation. Fast and slow permeation behavior can be readily recognized from the slope of the initial intensity drop. Absolute permeability coefficients of analytes can be obtained by knowledge of the binding affinity between analyte and the reporter pair. The method validation demonstrates that RT-PAMPA can be used robustly in aqueous solution and with organic cosolvents, including DMSO. Moreover, RT-PAMPA can be flexibly modified to monitor various analyte classes by changing to a suitable reporter pair. It is also possible to monitor permeation through different lipid compositions characteristic for different biological barriers.</p> <a id="h6" name="h6"></a><h2>Data Availability Statement</h2> <p class="mb0">The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.</p> <a id="h7" name="h7"></a><h2>Author Contributions</h2> <p class="mb0">SH and WN designed the project and experiments. SH and AZ performed all PAMPA and screening experiments. AB-B performed the synthesis of MDAP. AH instructed preliminary experiments with valuable findings. SH and WN wrote the manuscript. All authors contributed to the article and approved the submitted version.</p> <a id="h8" name="h8"></a><h2>Funding</h2> <p class="mb0">This work was supported by the Deutsche Forschungsgemeinschaft (DFG grants #NA-686/11 for WN and #HE 5967/4-1 for AH).</p> <a id="h9" name="h9"></a><h2>Conflict of Interest</h2> <p class="mb15">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p> <p class="mb0">The handling editor declared a past collaboration with the authors AH and WN.</p> <a id="h10" name="h10"></a><h2>Acknowledgments</h2> <p class="mb0">The authors thank Solène Collin and Nader Al Danaf for preliminary experiments and Dr. Frank Biedermann for encouraging the use of the MDAP∙CB8 receptor.</p> <a id="h11" name="h11"></a><h2>Supplementary Material</h2> <p class="mb0" id="SM1">The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fchem.2020.597927/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fchem.2020.597927/full#supplementary-material</a></p> <a id="h12" name="h12"></a><h2>References</h2> <div class="References"> <p class="ReferencesCopy1"><a name="B1" id="B1"></a> Arena, G., Gentile, S., Gulino, F. G., Sciotto, D., and Sgarlata, C. (2004). Water-soluble pentasulfonatocalix[5]arene: selective recognition of ditopic trimethylammonium cations by a triple non-covalent interaction. <i>Tetrahedron Lett.</i> 45, 7091–7094. doi: 10.1016/j.tetlet.2004.07.108</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1016/j.tetlet.2004.07.108" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=G.+Arena&author=S.+Gentile&author=F.+G.+Gulino&author=D.+Sciotto&author=C.+Sgarlata+&publication_year=2004&title=Water-soluble+pentasulfonatocalix[5]arene%3A+selective+recognition+of+ditopic+trimethylammonium+cations+by+a+triple+non-covalent+interaction&journal=Tetrahedron+Lett.&volume=45&pages=7091-7094" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B2" id="B2"></a> Artursson, P., Palm, K., and Luthman, K. (2001). Caco-2 monolayers in experimental and theoretical predictions of drug transport. <i>Adv. Drug Deliv. Rev.</i> 46, 27–43. doi: 10.1016/S0169-409X(00)00128-9</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/11259831" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/S0169-409X(00)00128-9" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=P.+Artursson&author=K.+Palm&author=K.+Luthman+&publication_year=2001&title=Caco-2+monolayers+in+experimental+and+theoretical+predictions+of+drug+transport&journal=Adv.+Drug+Deliv.+Rev.&volume=46&pages=27-43" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B3" id="B3"></a> Assaf, K. I., Begaj, B., Frank, A., Nilam, M., Mougharbel, A. S., Kortz, U., et al. (2019). High-affinity binding of metallacarborane cobalt bis(dicarbollide) anions to cyclodextrins and application to membrane translocation. <i>J. Org. Chem.</i> 84, 11790–11798. doi: 10.1021/acs.joc.9b01688</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/31274306" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/acs.joc.9b01688" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=K.+I.+Assaf&author=B.+Begaj&author=A.+Frank&author=M.+Nilam&author=A.+S.+Mougharbel&author=U.+Kortz+&publication_year=2019&title=High-affinity+binding+of+metallacarborane+cobalt+bis(dicarbollide)+anions+to+cyclodextrins+and+application+to+membrane+translocation&journal=J.+Org.+Chem.&volume=84&pages=11790-11798" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B4" id="B4"></a> Avdeef, A. (2003). <i>Absorption and Drug Development</i>. New York, NY: John Wiley & Sons, Inc.</p> <p class="ReferencesCopy2"><a href="http://scholar.google.com/scholar_lookup?author=A.+Avdeef+&publication_year=2003&title=Absorption+and+Drug+Development" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B5" id="B5"></a> Avdeef, A., Ruiz, A., Nalda, R., Ruell, J. A., Tsinman, O., Gonzalez, I., et al. (2004). PAMPA - a drug absorption in vitro model: 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. <i>Eur. J. Pharm. Sci.</i> 21, 429–441. doi: 10.1016/j.ejps.2003.10.009</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/14998573" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.ejps.2003.10.009" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=A.+Avdeef&author=A.+Ruiz&author=R.+Nalda&author=J.+A.+Ruell&author=O.+Tsinman&author=I.+Gonzalez+&publication_year=2004&title=PAMPA+-+a+drug+absorption+in+vitro+model%3A+7.+Comparing+rat+in+situ,+Caco-2,+and+PAMPA+permeability+of+fluoroquinolones&journal=Eur.+J.+Pharm.+Sci.&volume=21&pages=429-441" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B6" id="B6"></a> Barba-Bon, A., Pan, Y.-C., Biedermann, F., Guo, D. -S., Nau, W. M., and Hennig, A. (2019). Fluorescence monitoring of peptide transport pathways into large and giant vesicles by supramolecular host-dye pairs. <i>J. Am. Chem. Soc.</i> 141, 20137–20145. doi: 10.1021/jacs.9b09563</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/31739668" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/jacs.9b09563" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=A.+Barba-Bon&author=Y.+-C.+Pan&author=F.+Biedermann&author=D.++-S.+Guo&author=W.+M.+Nau&author=A.+Hennig+&publication_year=2019&title=Fluorescence+monitoring+of+peptide+transport+pathways+into+large+and+giant+vesicles+by+supramolecular+host-dye+pairs&journal=J.+Am.+Chem.+Soc.&volume=141&pages=20137-20145" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B7" id="B7"></a> Berben, P., Bauer-Brandl, A., Brandl, M., Faller, B., Flaten, G., Jacobsen, A., et al. (2018). Drug permeability profiling using cell-free permeation tools: overview and applications. <i>Eur. J. Pharm. Sci.</i> 119, 219–233. doi: 10.1016/j.ejps.2018.04.016</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/29660464" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.ejps.2018.04.016" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=P.+Berben&author=A.+Bauer-Brandl&author=M.+Brandl&author=B.+Faller&author=G.+Flaten&author=A.+Jacobsen+&publication_year=2018&title=Drug+permeability+profiling+using+cell-free+permeation+tools%3A+overview+and+applications&journal=Eur.+J.+Pharm.+Sci.&volume=119&pages=219-233" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B8" id="B8"></a> Biedermann, F., Ghale, G., Hennig, A., and Nau, W. M. (2020). Fluorescent artificial receptor-based membrane assay (FARMA) for spatiotemporally resolved monitoring of biomembrane permeability. <i>Commun. Biol.</i> 3:383. doi: 10.1038/s42003-020-1108-9</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/32669621" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1038/s42003-020-1108-9" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=F.+Biedermann&author=G.+Ghale&author=A.+Hennig&author=W.+M.+Nau+&publication_year=2020&title=Fluorescent+artificial+receptor-based+membrane+assay+(FARMA)+for+spatiotemporally+resolved+monitoring+of+biomembrane+permeability&journal=Commun.+Biol.&volume=3&pages=383" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B9" id="B9"></a> Biedermann, F., Hathazi, D., and Nau, W. M. (2015). Associative chemosensing by fluorescent macrocycle-dye complexes - a versatile enzyme assay platform beyond indicator displacement. <i>Chem. Commun.</i> 51, 4977–4980. doi: 10.1039/C4CC10227D</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/25622263" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1039/C4CC10227D" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=F.+Biedermann&author=D.+Hathazi&author=W.+M.+Nau+&publication_year=2015&title=Associative+chemosensing+by+fluorescent+macrocycle-dye+complexes+-+a+versatile+enzyme+assay+platform+beyond+indicator+displacement&journal=Chem.+Commun.&volume=51&pages=4977-4980" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B10" id="B10"></a> Cejas, M. A., and Raymo, F. M. (2005). Fluorescent diazapyrenium films and their response to dopamine. <i>Langmuir.</i> 21, 5795–5802. doi: 10.1021/la0502793</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/15952825" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/la0502793" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+A.+Cejas&author=F.+M.+Raymo+&publication_year=2005&title=Fluorescent+diazapyrenium+films+and+their+response+to+dopamine&journal=Langmuir.&volume=21&pages=5795-5802" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B11" id="B11"></a> Faller, B. (2008). Artificial membrane assays to assess permeability. <i>Curr. Drug Metab.</i> 9, 886–892. doi: 10.2174/138920008786485227</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/18991585" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.2174/138920008786485227" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=B.+Faller+&publication_year=2008&title=Artificial+membrane+assays+to+assess+permeability&journal=Curr.+Drug+Metab.&volume=9&pages=886-892" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B12" id="B12"></a> Florea, M., Kudithipudi, S., Rei, A., González-Álvarez, M. J., Jeltsch, A., and Nau, W. M. (2012). A fluorescence-based supramolecular tandem assay for monitoring lysine methyltransferase activity in homogeneous solution. <i>Chem. Eur. J.</i> 18, 3521–3528. doi: 10.1002/chem.201103397</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/22367964" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1002/chem.201103397" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Florea&author=S.+Kudithipudi&author=A.+Rei&author=M.+J.+González-Álvarez&author=A.+Jeltsch&author=W.+M.+Nau+&publication_year=2012&title=A+fluorescence-based+supramolecular+tandem+assay+for+monitoring+lysine+methyltransferase+activity+in+homogeneous+solution&journal=Chem.+Eur.+J.&volume=18&pages=3521-3528" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B13" id="B13"></a> Florea, M., and Nau, W. M. (2011). Strong binding of hydrocarbons to cucurbituril probed by fluorescent dye displacement: a supramolecular gas-sensing ensemble. <i>Angew. Chem. Int. Ed.</i> 50, 9338–9342. doi: 10.1002/anie.201104119</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/21948429" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1002/anie.201104119" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Florea&author=W.+M.+Nau+&publication_year=2011&title=Strong+binding+of+hydrocarbons+to+cucurbituril+probed+by+fluorescent+dye+displacement%3A+a+supramolecular+gas-sensing+ensemble&journal=Angew.+Chem.+Int.+Ed.&volume=50&pages=9338-9342" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B14" id="B14"></a> Fujikawa, M., Nakao, K., Shimizu, R., and Akamatsu, M. (2007). QSAR study on permeability of hydrophobic compounds with artificial membranes. <i>Bioorg. Med. Chem.</i> 15, 3756–3767. doi: 10.1016/j.bmc.2007.03.040</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/17418579" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.bmc.2007.03.040" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Fujikawa&author=K.+Nakao&author=R.+Shimizu&author=M.+Akamatsu+&publication_year=2007&title=QSAR+study+on+permeability+of+hydrophobic+compounds+with+artificial+membranes&journal=Bioorg.+Med.+Chem.&volume=15&pages=3756-3767" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B15" id="B15"></a> Ghale, G., Lanctôt, A. G., Kreissl, H. T., Jacob, M. H., Weingart, H., Winterhalter, M., et al. (2014). Chemosensing ensembles for monitoring biomembrane transport in real time. <i>Angew. Chem. Int. Ed.</i> 53, 2762–2765. doi: 10.1002/anie.201309583</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/24469927" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1002/anie.201309583" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=G.+Ghale&author=A.+G.+Lanctôt&author=H.+T.+Kreissl&author=M.+H.+Jacob&author=H.+Weingart&author=M.+Winterhalter+&publication_year=2014&title=Chemosensing+ensembles+for+monitoring+biomembrane+transport+in+real+time&journal=Angew.+Chem.+Int.+Ed.&volume=53&pages=2762-2765" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B16" id="B16"></a> Ghale, G., and Nau, W. M. (2014). Dynamically analyte-responsive macrocyclic host-fluorophore systems. <i>Acc. Chem. Res.</i> 47, 2150–2159. doi: 10.1021/ar500116d</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/24785659" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/ar500116d" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=G.+Ghale&author=W.+M.+Nau+&publication_year=2014&title=Dynamically+analyte-responsive+macrocyclic+host-fluorophore+systems&journal=Acc.+Chem.+Res.&volume=47&pages=2150-2159" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B17" id="B17"></a> Ghale, G., Ramalingam, V., Urbach, A. R., and Nau, W. M. (2011). Determining protease substrate selectivity and inhibition by label-free supramolecular tandem enzyme assays. <i>J. Am. Chem. Soc.</i> 133, 7528–7535. doi: 10.1021/ja2013467 </p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1021/ja2013467" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=G.+Ghale&author=V.+Ramalingam&author=A.+R.+Urbach&author=W.+M.+Nau+&publication_year=2011&title=Determining+protease+substrate+selectivity+and+inhibition+by+label-free+supramolecular+tandem+enzyme+assays&journal=J.+Am.+Chem.+Soc.&volume=133&pages=7528-7535" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B18" id="B18"></a> Guo, D. -S., Uzunova, V. D., Su, X., Liu, Y., and Nau, W. M. (2011). Operational calixarene-based fluorescent sensing systems for choline and acetylcholine and their application to enzymatic reactions. <i>Chem. Sci.</i> 2, 1722–1734. doi: 10.1039/c1sc00231g</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1039/c1sc00231g" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=D.++-S.+Guo&author=V.+D.+Uzunova&author=X.+Su&author=Y.+Liu&author=W.+M.+Nau+&publication_year=2011&title=Operational+calixarene-based+fluorescent+sensing+systems+for+choline+and+acetylcholine+and+their+application+to+enzymatic+reactions&journal=Chem.+Sci.&volume=2&pages=1722-1734" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B19" id="B19"></a> Guo, D. -S., Wang, K., and Liu, Y. (2008). Selective binding behaviors of p-sulfonatocalixarenes in aqueous solution. <i>J. Incl. Phenom. Macrocycl. Chem</i>. 62, 1–21. doi: 10.1007/s10847-008-9452-2</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1007/s10847-008-9452-2" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=D.++-S.+Guo&author=K.+Wang&author=Y.+Liu+&publication_year=2008&title=Selective+binding+behaviors+of+p-sulfonatocalixarenes+in+aqueous+solution&journal=J.+Incl.+Phenom.+Macrocycl.+Chem&volume=62&pages=1-21" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B20" id="B20"></a> Hanlan, L., Chantel, S., Guy, C., Chao, D., Avdeef, A., and Tischler, M. (2003). In vitro permeability of poorly aqueous soluble compounds using different solubilizers in the PAMPA assay with liquid chromatography/mass spectrometry detection. <i>Pharm Res.</i> 20, 1820–1826. doi: 10.1023/B:PHAM.0000003380.44755.5a</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1023/B:PHAM.0000003380.44755.5a" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=L.+Hanlan&author=S.+Chantel&author=C.+Guy&author=D.+Chao&author=A.+Avdeef&author=M.+Tischler+&publication_year=2003&title=In+vitro+permeability+of+poorly+aqueous+soluble+compounds+using+different+solubilizers+in+the+PAMPA+assay+with+liquid+chromatography%2Fmass+spectrometry+detection&journal=Pharm+Res.&volume=20&pages=1820-1826" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B21" id="B21"></a> Hayeshi, R., Hilgendorf, C., Artursson, P., Augustijns, P., Brodin, B., Dehertogh, P., et al. (2008). Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories. <i>Eur. J. Pharm. Sci.</i> 35, 383–396. doi: 10.1016/j.ejps.2008.08.004</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/18782614" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.ejps.2008.08.004" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=R.+Hayeshi&author=C.+Hilgendorf&author=P.+Artursson&author=P.+Augustijns&author=B.+Brodin&author=P.+Dehertogh+&publication_year=2008&title=Comparison+of+drug+transporter+gene+expression+and+functionality+in+Caco-2+cells+from+10+different+laboratories&journal=Eur.+J.+Pharm.+Sci.&volume=35&pages=383-396" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B22" id="B22"></a> Hou, T. J., Zhang, W., Xia, K., Qiao, X. B., and Xu, X. J. (2004). ADME evaluation in drug discovery. 5. correlation of Caco-2 permeation with simple molecular properties. <i>J. Chem. Inf. Comput. Sci.</i> 44, 1585–1600. doi: 10.1021/ci049884m</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/15446816" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/ci049884m" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=T.+J.+Hou&author=W.+Zhang&author=K.+Xia&author=X.+B.+Qiao&author=X.+J.+Xu+&publication_year=2004&title=ADME+evaluation+in+drug+discovery.+5.+correlation+of+Caco-2+permeation+with+simple+molecular+properties&journal=J.+Chem.+Inf.+Comput.+Sci.&volume=44&pages=1585-1600" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B23" id="B23"></a> Kansy, M., Senner, F., and Gubernator, K. (1998). Physicochemical high throughput screening: parallel artificial membrane permeability assay in the description of passive absorption processes. <i>J. Med. Chem.</i> 41, 1070–1110. doi: 10.1021/jm970530e</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/9544199" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/jm970530e" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Kansy&author=F.+Senner&author=K.+Gubernator+&publication_year=1998&title=Physicochemical+high+throughput+screening%3A+parallel+artificial+membrane+permeability+assay+in+the+description+of+passive+absorption+processes&journal=J.+Med.+Chem.&volume=41&pages=1070-1110" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B24" id="B24"></a> Márquez, C., Fang, H., and Nau, W. M. (2004). Cucurbiturils: molecular nanocapsules for time-resolved fluorescence-based assays. <i>IEEE Trans. NanoBiosci.</i> 3, 39–45. doi: 10.1109/TNB.2004.824269</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/15382642" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1109/TNB.2004.824269" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=C.+Márquez&author=H.+Fang&author=W.+M.+Nau+&publication_year=2004&title=Cucurbiturils%3A+molecular+nanocapsules+for+time-resolved+fluorescence-based+assays&journal=IEEE+Trans.+NanoBiosci.&volume=3&pages=39-45" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B25" id="B25"></a> Megyesi, M., Biczók, L., and Jablonkai, I. (2008). Highly sensitive fluorescence response to inclusion complex formation of berberine alkaloid with cucurbit[7]uril. <i>J. Phys. Chem. C.</i> 112, 3410–3416. doi: 10.1021/jp075348w</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1021/jp075348w" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Megyesi&author=L.+Biczók&author=I.+Jablonkai+&publication_year=2008&title=Highly+sensitive+fluorescence+response+to+inclusion+complex+formation+of+berberine+alkaloid+with+cucurbit[7]uril&journal=J.+Phys.+Chem.+C.&volume=112&pages=3410-3416" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B26" id="B26"></a> Moghaddam, S., Yang, C., Rekharsky, M., Ko, Y. H., Kim, K., Inoue, Y., et al. (2011). New ultrahigh affinity host-guest complexes of cucurbit[7]uril with bicyclo[2.2.2]octane and adamantane guests: thermodynamic analysis and evaluation of M2 affinity calculations. <i>J. Am. Chem. Soc.</i> 133, 3570–3581. doi: 10.1021/ja109904u</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/21341773" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/ja109904u" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=S.+Moghaddam&author=C.+Yang&author=M.+Rekharsky&author=Y.+H.+Ko&author=K.+Kim&author=Y.+Inoue+&publication_year=2011&title=New+ultrahigh+affinity+host-guest+complexes+of+cucurbit[7]uril+with+bicyclo[2.2.2]octane+and+adamantane+guests%3A+thermodynamic+analysis+and+evaluation+of+M2+affinity+calculations&journal=J.+Am.+Chem.+Soc.&volume=133&pages=3570-3581" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B27" id="B27"></a> Nielsen, P. E., and Avdeef, A. (2004). PAMPA-a drug absorption in vitro model 8. Apparent filter porosity and the unstirred water layer. <i>Eur. J. Pharm. Sci.</i> 22, 33–41. doi: 10.1016/j.ejps.2004.02.003</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/15113581" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.ejps.2004.02.003" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=P.+E.+Nielsen&author=A.+Avdeef+&publication_year=2004&title=PAMPA-a+drug+absorption+in+vitro+model+8.+Apparent+filter+porosity+and+the+unstirred+water+layer&journal=Eur.+J.+Pharm.+Sci.&volume=22&pages=33-41" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B28" id="B28"></a> Norouzy, A., Azizi, Z., and Nau, W. M. (2015). Indicator displacement assays inside live cells. <i>Angew. Chem. Int. Ed.</i> 54, 792–795. doi: 10.1002/anie.201407808</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/25430503" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1002/anie.201407808" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=A.+Norouzy&author=Z.+Azizi&author=W.+M.+Nau+&publication_year=2015&title=Indicator+displacement+assays+inside+live+cells&journal=Angew.+Chem.+Int.+Ed.&volume=54&pages=792-795" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B29" id="B29"></a> Oja, M., and Maran, U. (2015). Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds. <i>SAR QSAR Environ. Res.</i> 26, 701–719. doi: 10.1080/1062936X.2015.1085896</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/26383235" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1080/1062936X.2015.1085896" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=M.+Oja&author=U.+Maran+&publication_year=2015&title=Quantitative+structure-permeability+relationships+at+various+pH+values+for+acidic+and+basic+drugs+and+drug-like+compounds&journal=SAR+QSAR+Environ.+Res.&volume=26&pages=701-719" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B30" id="B30"></a> Sindelar, V., Cejas, M. A., Raymo, F. M., Chen, W., Parker, S. E., and Kaifer, A. E. (2005). Supramolecular assembly of 2,7-dimethyldiazapyrenium and cucurbit[8]uril: a new fluorescent host for detection of catechol and dopamine. <i>Chem. Eur. J.</i> 11, 7054–7059. doi: 10.1002/chem.200500917</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/16175642" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1002/chem.200500917" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=V.+Sindelar&author=M.+A.+Cejas&author=F.+M.+Raymo&author=W.+Chen&author=S.+E.+Parker&author=A.+E.+Kaifer+&publication_year=2005&title=Supramolecular+assembly+of+2,7-dimethyldiazapyrenium+and+cucurbit[8]uril%3A+a+new+fluorescent+host+for+detection+of+catechol+and+dopamine&journal=Chem.+Eur.+J.&volume=11&pages=7054-7059" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B31" id="B31"></a> Sinn, S., and Biedermann, F. (2018). Chemical sensors based on cucurbit[n]uril macrocycles. <i>Isr. J. Chem.</i> 58, 357–412. doi: 10.1002/ijch.201700118</p> <p class="ReferencesCopy2"><a href="https://doi.org/10.1002/ijch.201700118" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=S.+Sinn&author=F.+Biedermann+&publication_year=2018&title=Chemical+sensors+based+on+cucurbit[n]uril+macrocycles&journal=Isr.+J.+Chem.&volume=58&pages=357-412" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B32" id="B32"></a> Sugano, K., Hamada, H., Machida, M., and Ushio, H. (2001). High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeability assay. <i>J. Biomolec. Screen.</i> 6, 189–196. doi: 10.1177/108705710100600309</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/11689115" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1177/108705710100600309" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=K.+Sugano&author=H.+Hamada&author=M.+Machida&author=H.+Ushio+&publication_year=2001&title=High+throughput+prediction+of+oral+absorption%3A+improvement+of+the+composition+of+the+lipid+solution+used+in+parallel+artificial+membrane+permeability+assay&journal=J.+Biomolec.+Screen.&volume=6&pages=189-196" target="_blank">Google Scholar</a></p> </div> <div class="References"> <p class="ReferencesCopy1"><a name="B33" id="B33"></a> Wohnsland, F., and Faller, B. (2001). High-throughput permeability pH profile and high-throughput alkane/water log <i>P</i> with artificial membranes. <i>J. Med. Chem.</i> 44, 923–930. doi: 10.1021/jm001020e</p> <p class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/11300874" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1021/jm001020e" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=F.+Wohnsland&author=B.+Faller+&publication_year=2001&title=High-throughput+permeability+pH+profile+and+high-throughput+alkane%2Fwater+log+P+with+artificial+membranes&journal=J.+Med.+Chem.&volume=44&pages=923-930" target="_blank">Google Scholar</a></p> </div> </div> <div class="thinLineM20"></div> <div class="AbstractSummary"> <p><span>Keywords:</span> drug discovery, permeability, fluorescence, cucurbituril, passive diffusion</p> <p><span>Citation:</span> He S, Zhiti A, Barba-Bon A, Hennig A and Nau WM (2020) Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors. <i>Front. Chem.</i> 8:597927. doi: 10.3389/fchem.2020.597927</p> <p id="timestamps"><span>Received:</span> 22 August 2020; <span>Accepted:</span> 06 October 2020;<br> <span>Published:</span> 03 November 2020.</p> <div><p>Edited by:</p> <a href="http://loop.frontiersin.org/people/695885/overview">Chusen Huang</a>, Shanghai Normal University, China</div> <div><p>Reviewed by:</p> <a href="http://loop.frontiersin.org/people/924033/overview">Haibo Zhang</a>, Wuhan University, China<br> <a href="http://loop.frontiersin.org/people/645119/overview">Adam Charles Sedgwick</a>, University of Texas at Austin, United States</div> <p><span>Copyright</span> © 2020 He, Zhiti, Barba-Bon, Hennig and Nau. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p> <p><span>*Correspondence:</span> Suhang He, <a id="encmail">cy5oZUBqYWNvYnMtdW5pdmVyc2l0eS5kZQ==</a>; Werner M. Nau, <a id="encmail">dy5uYXVAamFjb2JzLXVuaXZlcnNpdHkuZGU=</a></p> <div class="clear"></div> </div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/695885/32" alt="Chusen Huang" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Chusen Huang </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Shanghai Normal University, China </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/645119/overview" data-event="editorInfo-a-adamCharlesSedgwick" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/645119/32" alt="Adam Charles Sedgwick" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Adam Charles Sedgwick </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> The University of Texas at Austin, United States </div></div></a><a href="https://loop.frontiersin.org/people/924033/overview" data-event="editorInfo-a-haiboZhang" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/924033/32" alt="Haibo Zhang" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Haibo Zhang </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Wuhan University, China </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"> <li><a href="#h1">Abstract</a></li> <li><a href="#h2">Introduction</a></li> <li><a href="#h3">Materials and Methods</a></li> <li><a href="#h4">Results and Discussion</a></li> <li><a href="#h5">Conclusions</a></li> <li><a href="#h6">Data Availability Statement</a></li> <li><a href="#h7">Author Contributions</a></li> <li><a href="#h8">Funding</a></li> <li><a href="#h9">Conflict of Interest</a></li> <li><a href="#h10">Acknowledgments</a></li> <li><a href="#h11">Supplementary Material</a></li> <li><a href="#h12">References</a></li> </ul></div></div>  <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeOutline ActionsDropDown__button--iconQuote"><span class="ActionsDropDown__button__label">Export citation</span></button> <div class="ActionsDropDown__menuWrapper"> <ul class="ActionsDropDown__menu"><li><a 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It explores the role of chemistry in our everyday lives - from electronic devices to health and wellbeing.",mission:"\u003Cp\u003EFrontiers in Chemistry is a PubMed Central (PMC), Scopus and Web of Science (SCIE) indexed journal that explores the role of chemistry in our everyday lives.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Prof Steve Suib (University of Connecticut, USA), Frontiers in Chemistry welcomes original research articles, review articles, commentaries, and ideas about all aspects of chemistry, from electronics and manufacturing to health and well-being. The journal covers all areas of the chemical sciences and aims to advance our understanding of how atoms, ions, and molecules come together and come apart.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Chemistry covers a wide range of topics including, but not limited to:\u003C\u002Fp\u003E\n\n\u003Cul\u003E\n \u003Cli\u003Eanalytical chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Eastrochemistry\u003C\u002Fli\u003E\n \u003Cli\u003Ecatalytic reactions and chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Echemical biology\u003C\u002Fli\u003E\n \u003Cli\u003Echemical physics and physical chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Eelectrochemistry\u003C\u002Fli\u003E\n \u003Cli\u003Egreen and sustainable chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Einorganic chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Emedicinal and pharmaceutical chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Emolecular liquids\u003C\u002Fli\u003E\n \u003Cli\u003Enanoscience\u003C\u002Fli\u003E\n \u003Cli\u003Eorganic chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Eorganometallic chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Ephotocatalysis and photochemistry\u003C\u002Fli\u003E\n \u003Cli\u003Epolymer chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Eporous crystalline networks\u003C\u002Fli\u003E\n \u003Cli\u003Esolid state chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Esupramolecular chemistry\u003C\u002Fli\u003E\n \u003Cli\u003Etheoretical and computational chemistry.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003ECollaborative research across areas of Chemistry is highly encouraged, particularly those covering specific subdisciplines such as analytical, inorganic, organic and physical chemistries. The journal actively welcomes submissions which support and advance the UN’s Sustainable Development Goals (SDGs), notably SDG 9: industry, innovation and infrastructure.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus primarily on biological or medical applications, such as cell culture studies, cancer research, tissue engineering, or drug delivery systems, are not suitable for publication in this journal. Similarly, studies that are primarily concerned with the physical properties of materials, such as Fourier transform or photoelectron spectroscopy, without a relevance to chemical principles or reactions, are also outside the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Chemistry is committed to advancing developments in the field by allowing unrestricted access to articles and communicating scientific knowledge to researchers and the public alike, to enable the scientific breakthroughs of the future.\u003C\u002Fp\u003E\n\n\u003Cp\u003EAuthors are encouraged to submit the Characterization Checklist alongside their manuscript (.xlsx file). This will not be published, but helps Review Editors and Associate Editors to assess the completeness of the presented data.\u003C\u002Fp\u003E",palette:"red",impactFactor:"5.5",citeScore:"7.3",citations:"110000",showTagline:e,twitter:"@FrontChemistry",__typename:"Journal"},currentFrontiersJournal:{id:q,name:n,slug:r,printISSN:e,shortName:K,electronicISSN:L,abbreviation:$,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:A,domainId:c,__typename:aa},__typename:a},articleHubSlug:g,articleHubPage:M,currentArticle:{id:597927,doi:ab,title:N,acceptanceDate:new Date(1601987043000),receptionDate:new Date(1598118975000),publicationDate:new Date(1604361600000),isPublished:h,abstract:ac,researchTopic:{id:12704,title:"Supramolecular Ensembles Modified by Small Organic Molecules for Biosensing and Therapy",articlesCount:O,isMagazinePage:l,slug:"supramolecular-ensembles-modified-by-small-organic-molecules-for-biosensing-and-therapy",isOpenForSubmission:l},articleType:{id:24,name:"Original Research"},stage:{id:P,name:g},keywords:["Drug Discovery","Permeability",ad,"cucurbituril","Passive diffusion"],authors:[{id:ae,firstName:af,lastName:"He",givenNames:af,isCorresponding:l,isProfilePublic:h,userId:ae,affiliations:[{organizationName:s,countryName:t,cityName:g,stateName:g,zipCode:g}]},{id:m,firstName:ag,lastName:"Zhiti",givenNames:ag,isCorresponding:l,isProfilePublic:l,userId:m,affiliations:[{organizationName:s,countryName:t,cityName:g,stateName:g,zipCode:g}]},{id:ah,firstName:ai,lastName:"Barba-Bon",givenNames:ai,isCorresponding:l,isProfilePublic:h,userId:ah,affiliations:[{organizationName:s,countryName:t,cityName:g,stateName:g,zipCode:g}]},{id:aj,firstName:ak,lastName:"Hennig",givenNames:ak,isCorresponding:l,isProfilePublic:h,userId:aj,affiliations:[{organizationName:s,countryName:t,cityName:g,stateName:g,zipCode:g}]},{id:al,firstName:am,lastName:"Nau",givenNames:am,isCorresponding:l,isProfilePublic:h,userId:al,affiliations:[{organizationName:s,countryName:t,cityName:g,stateName:g,zipCode:g}]}],editors:[{id:an,firstName:ao,lastName:"Huang",givenNames:ao,isCorresponding:l,isProfilePublic:h,userId:an,affiliations:[{organizationName:"Shanghai Normal University",countryName:ap,cityName:g,stateName:g,zipCode:g}]}],reviewers:[{id:aq,firstName:"Adam",lastName:"Sedgwick",givenNames:"Adam Charles",isCorresponding:l,isProfilePublic:h,userId:aq,affiliations:[{organizationName:"The University of Texas at Austin",countryName:"United States",cityName:g,stateName:g,zipCode:g}]},{id:ar,firstName:as,lastName:"Zhang",givenNames:as,isCorresponding:l,isProfilePublic:h,userId:ar,affiliations:[{organizationName:"Wuhan University",countryName:ap,cityName:g,stateName:g,zipCode:g}]}],journal:{id:q,slug:r,name:n,shortName:K,electronicISSN:L,field:{id:A,domainId:c,__typename:aa},specialtyId:e,journalSectionPaths:[{section:at,__typename:"journal_journalSectionPath"}],__typename:a},section:at,impactMetrics:{views:15014,downloads:2003,citations:19},volume:ax,articleVolume:"Volume 8 - 2020",relatedArticles:[],isPublishedV2:l,contents:{titleHtml:N,fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\n\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F948913\" class=\"user-id-948913\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F948913\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"\\nSuhang He
\"\u003ESuhang He\u003C\u002Fa\u003E\u003Csup\u003E*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Anxhela Zhiti\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EAnxhela Zhiti\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1120234\" class=\"user-id-1120234\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1120234\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Andrea Barba-Bon\"\u003EAndrea Barba-Bon\u003C\u002Fa\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F921762\" class=\"user-id-921762\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F921762\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Andreas Hennig\"\u003EAndreas Hennig\u003C\u002Fa\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F500593\" class=\"user-id-500593\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F500593\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Werner M. Nau
\"\u003EWerner M. Nau\u003C\u002Fa\u003E\u003Csup\u003E*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\n\u003Cul class=\"notes\"\u003E\u003Cli class=\"pl0\"\u003EDepartment of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\u003Cp\u003EParallel artificial membrane permeability assay (PAMPA) is a screening tool for the evaluation of drug permeability across various biological membrane systems in a microplate format. In PAMPA, a drug candidate is allowed to pass through the lipid layer of a particular well during an incubation period of, typically, 10–16 h. In a second step, the samples of each well are transferred to a UV-Vis–compatible microplate and optically measured (applicable only to analytes with sufficient absorbance) or sampled by mass-spectrometric analysis. The required incubation period, sample transfer, and detection methods jointly limit the scalability of PAMPA to high-throughput screening format. We introduce a modification of the PAMPA method that allows direct fluorescence detection, without sample transfer, in real time (RT-PAMPA). The method employs the use of a fluorescent artificial receptor (FAR), composed of a macrocycle in combination with an encapsulated fluorescent dye, administered in the acceptor chamber of conventional PAMPA microplates. Because the detection principle relies on the molecular recognition of an analyte by the receptor and the associated fluorescence response, concentration changes of any analyte that binds to the receptor can be monitored (molecules with aromatic residues in the present example), regardless of the spectroscopic properties of the analyte itself. Moreover, because the fluorescence of the (upper) acceptor well can be read out directly by fluorescence in a microplate reader, the permeation of the drug through the planar lipid layer can be monitored in real time. Compared with the traditional assay, RT-PAMPA allows not only quantification of the permeability characteristics but also rapid differentiation between fast and slow diffusion events.\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"JournalFullText\"\u003E\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EDrug absorption is a key factor in the evaluation of potential active pharmaceutical ingredients at the early stage of drug development. For orally administered drugs, the solubility and permeability in the gastrointestinal system determine whether the drug concentration can reach a sufficient therapeutic physiological level. The permeability of a drug is commonly estimated with empirical physicochemical chemometric methods (e.g., QSAR models) (\u003Ca href=\"#B22\"\u003EHou et al., 2004\u003C\u002Fa\u003E), cell-based assays (Caco-2 assay) (\u003Ca href=\"#B2\"\u003EArtursson et al., 2001\u003C\u002Fa\u003E), or artificial membrane–based assays [e.g., parallel artificial membrane permeability assay (PAMPA)] (\u003Ca href=\"#B23\"\u003EKansy et al., 1998\u003C\u002Fa\u003E; \u003Ca href=\"#B11\"\u003EFaller, 2008\u003C\u002Fa\u003E). While the cellular Caco-2 model is a highly informative screening model, there are limitations such as long differentiation period, poor interlaboratory reproducibility, and economic considerations (\u003Ca href=\"#B21\"\u003EHayeshi et al., 2008\u003C\u002Fa\u003E). PAMPA has been introduced 20 years ago as a complementary tool to evaluate the passive transportation of drugs; the assay is conducted with specially designed and commercially available “sandwich-type” multiwell microplates, which consist of an acceptor plate and a donor plate that are separated by a lipid-infused microporous filter (\u003Ca href=\"#S1\"\u003EScheme 1A\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003ESCHEME 1\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" name=\"scheme1\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g004.jpg\" alt=\"www.frontiersin.org\" id=\"S1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EScheme 1. (A)\u003C\u002Fstrong\u003E Working principle of RT-PAMPA and \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E schematic representation, as well as chemical structures of CB8, MDAP (as \u003Cmath\u003E\u003Cmsubsup\u003E\u003Cmrow\u003E\u003Cmtext\u003EPF\u003C\u002Fmtext\u003E\u003C\u002Fmrow\u003E\u003Cmrow\u003E\u003Cmn\u003E6\u003C\u002Fmn\u003E\u003C\u002Fmrow\u003E\u003Cmrow\u003E\u003Cmo\u003E-\u003C\u002Fmo\u003E\u003C\u002Fmrow\u003E\u003C\u002Fmsubsup\u003E\u003C\u002Fmath\u003E salt), the MDAP∙CB8 complex, as well as the MDAP∙CB8∙analyte ternary complex.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cp class=\"mb15 w100pc float_left mt15\"\u003EPAMPA has been used in combination with, or as an alternative to the Caco-2 assay, to improve efficiency and reproducibility (\u003Ca href=\"#B7\"\u003EBerben et al., 2018\u003C\u002Fa\u003E). Variables in PAMPA have been extensively studied, including the effect of stirring of the lower water layer, pH, and sink conditions. The thickness of the unstirred water layer, for example, is a critical parameter, especially for large drug molecules; in some circumstances, it can be a rate-limiting step (\u003Ca href=\"#B33\"\u003EWohnsland and Faller, 2001\u003C\u002Fa\u003E; \u003Ca href=\"#B27\"\u003ENielsen and Avdeef, 2004\u003C\u002Fa\u003E). The pH of the drug solution is another important factor, as the neutral form of a compound regularly has a larger permeability than the ionic one (\u003Ca href=\"#B29\"\u003EOja and Maran, 2015\u003C\u002Fa\u003E). Besides, the \u003Ci\u003Ein vivo\u003C\u002Fi\u003E absorptive sink condition (e.g., a pH gradient at the two sides of the membrane, blood flow, and serum proteins) has also been considered, which led to the development of the double-sink PAMPA method, as a variant (\u003Ca href=\"#B4\"\u003EAvdeef, 2003\u003C\u002Fa\u003E; \u003Ca href=\"#B5\"\u003EAvdeef et al., 2004\u003C\u002Fa\u003E). Because of its implementation as a single-point assay, the permeability value with PAMPA is obtained after a specific incubation time, typically 10–16 h (\u003Ca href=\"#B32\"\u003ESugano et al., 2001\u003C\u002Fa\u003E). At this end point, the permeation process is interrupted by separating the acceptor from the donor plate and the samples of the individual wells are transferred to microplates suitable for UV-Vis quantification; for drug candidates with insufficient UV-Vis absorption, liquid chromatography–mass spectrometry (LC\u002FMS) techniques are required for quantitative analysis, adding instrumental–analytical work for each and every well of analyte (\u003Ca href=\"#B20\"\u003EHanlan et al., 2003\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EIn this experimental study, we administer a fluorescent artificial receptor (FAR) into the acceptor well of PAMPA (\u003Ca href=\"#S1\"\u003EScheme 1A\u003C\u002Fa\u003E). The FAR is known to rapidly complex selected analytes by molecular recognition and thereby changes its fluorescence, either quenching or enhancement. Therefore, when the analyte is administered to the donor well of the PAMPA setup, its permeation through the artificial membrane connecting the acceptor and the donor plate can be followed in real time through a fluorescence intensity change, resulting in the setup of a real-time PAMPA (RT-PAMPA). From a chemical point of view, FARs are composed of a supramolecular reporter pair, that is, a macrocyclic host and a corresponding fluorescent dye molecule. Examples of commonly used FARs are 2,7-dimethyldiazapyrenium (MDAP) in combination with cucurbit[8]uril (CB8) (\u003Ca href=\"#B30\"\u003ESindelar et al., 2005\u003C\u002Fa\u003E), berberine in a pair with cucurbit[7]uril (\u003Ca href=\"#B25\"\u003EMegyesi et al., 2008\u003C\u002Fa\u003E), and lucigenin together with \u003Ci\u003Ep\u003C\u002Fi\u003E-sulfonato-calix[4]arene (\u003Ca href=\"#B18\"\u003EGuo et al., 2011\u003C\u002Fa\u003E). The sensing capabilities of these artificial receptors have already been demonstrated in the context of analyte transport through membrane porins (\u003Ca href=\"#B15\"\u003EGhale et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B3\"\u003EAssaf et al., 2019\u003C\u002Fa\u003E; \u003Ca href=\"#B6\"\u003EBarba-Bon et al., 2019\u003C\u002Fa\u003E), for binding constant measurements (\u003Ca href=\"#B13\"\u003EFlorea and Nau, 2011\u003C\u002Fa\u003E), for enzymatic reaction monitoring (\u003Ca href=\"#B17\"\u003EGhale et al., 2011\u003C\u002Fa\u003E), and to demonstrate analyte uptake into cells (\u003Ca href=\"#B28\"\u003ENorouzy et al., 2015\u003C\u002Fa\u003E). The different FARs can be further classified according to their operational principle (competitive and associative binding mechanism) (\u003Ca href=\"#B31\"\u003ESinn and Biedermann, 2018\u003C\u002Fa\u003E) or their phenomenological fluorescence intensity response upon analyte binding (“switch-on” vs. “switch-off”) (\u003Ca href=\"#B12\"\u003EFlorea et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B16\"\u003EGhale and Nau, 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B9\"\u003EBiedermann et al., 2015\u003C\u002Fa\u003E). Among those, the first one, MDAP∙CB8, emerged as the most broadly applicable one (see chemical structures in \u003Ca href=\"#S1\"\u003EScheme 1B\u003C\u002Fa\u003E), because it responds to a wide range of analytes with aromatic residues, which covers also numerous drugs and biomolecules of interest. The MDAP∙CB8 receptor operates through an associative mechanism (formation of a ternary complexes with the analyte, \u003Ca href=\"#S1\"\u003EScheme 1B\u003C\u002Fa\u003E), and it displays a switch-off fluorescence response, due to intracavity quenching of the dye in the ternary complex. It is noteworthy that our present technical implementation draws inspiration from a recent assay method (FAR membrane assays), which has originally been developed for liposomal solutions to monitor analyte permeation through the vesicular membranes (\u003Ca href=\"#B8\"\u003EBiedermann et al., 2020\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003ETo simplify the methodology in our present proof-of-concept study, the traditional PAMPA setup was employed, that is, without considering the unstirred water layers and sink conditions. As an important technical simplification of RT-PAMPA, the permeation process can be directly followed by measuring the fluorescence in the (upper) acceptor well in the microplate reader throughout the incubation period, that is, without the need to disassemble the plates as is common in the original UV-Vis and LC\u002FMS implementations. Accordingly, the RT-PAMPA method differs not only chemically, because of the utilization of FARs, but also operationally, because of the direct fluorescence read-out. The latter is especially helpful when dealing with fast permeating drugs, as the lag time until the first read-out can be significantly reduced. It is also possible, as an additional perspective, to extract mechanistically relevant information, because the actual permeation kinetics can be measured, e.g., to assess saturation or lag effects or to differentiate monoexponential from multiexponential kinetic profiles. We found that the resulting RT-PAMPA, employing MDAP∙CB8 as FAR, responds very sensitively to electron-rich aromatic structures, such as indole. The methodology has been validated with different lipid solutions, e.g., 1,2-dioleoyl-\u003Ci\u003Esn\u003C\u002Fi\u003E-glycero-3-phosphocholine (DOPC), and cosolvents, and was shown to work robustly under various test conditions.\u003C\u002Fp\u003E\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EMaterials and Methods\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003ECB8 was purchased from Strem Chemicals; the content was determined by \u003Csup\u003E1\u003C\u002Fsup\u003EH NMR integration. MDAP and cucurbit[7]uril were synthesized according to the literature methods (\u003Ca href=\"#B24\"\u003EMárquez et al., 2004\u003C\u002Fa\u003E; \u003Ca href=\"#B10\"\u003ECejas and Raymo, 2005\u003C\u002Fa\u003E). Berberine was purchased from Sigma–Aldrich and used without further purification. DOPC was purchased from TCI and used as received. Avanti PAMPA lipid blend I was purchased from Sigma; the lipid blend was a combination of DOPC and stearic acid at a ratio of 80:20 (wt\u002Fwt) and dissolved in dodecane with 1% ethanol. Analytes were purchased from Sigma–Aldrich or TCI and used without further purification. The 96-well Multiscreen IP filter plates (MAIPNTR10) were purchased from Merck Millipore, which are based on hydrophobic polyvinylidene fluoride as filter material. The donor plate was taken from the Corning Gentest precoated PAMPA system. For the screening experiments, 96-well black polystyrene microplates from Corning were used.\u003C\u002Fp\u003E\n\u003Ch3\u003EParallel Artificial Membrane Permeability Assay\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EAnalyte solutions were prepared at 1 mmol\u002FL in Millipore water or cosolvents as indicated. The MDAP∙CB8 reporter pair solution contained 5 μmol\u002FL of MDAP and 6 μmol\u002FL of CB8 that were dissolved in Millipore water. Two lipid solutions were used, including the commercial Avanti PAMPA lipid blend I and the self-prepared 2% DOPC in dodecane. To proceed with the assay, 5 μL of the lipid solution was pipetted to the microporous filter and allowed to impregnate evenly; 300 μL of the analyte solution was transferred to the lower donor well, and 100 μL of the reporter pair solution was transferred to the upper acceptor well. The acceptor plate was combined with the donor plate after the solutions had been loaded to define the start point of the assay. Fluorescence readings were taken on a Jasco FP-8500 fluorimeter equipped with a microplate reader with an excitation wavelength at 418 nm and monitored at an emission wavelength of 449 nm.\u003C\u002Fp\u003E\n\u003Ch3\u003EScreening Test\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EAnalyte screening and solvent effect studies were carried out in 96-well microplates; 150 μL of the reporter pair solution was pipetted into each well, followed by the addition of 15 μL of the analyte solution or solvent. For analytes that were insufficiently water-soluble but that dissolved with organic cosolvents, the final organic content was 2% after mixing with the reporter pair solution. Fluorescence was measured with the same parameters as for PAMPA. Intensity changes upon addition of the analyte solutions were recorded, and solvent-induced changes (background) were subtracted.\u003C\u002Fp\u003E\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EResults and Discussion\u003C\u002Fh2\u003E\n\u003Ch3 class=\"pt0\"\u003EAnalyte Screening\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EA recent report on the permeation of analytes across liposomal membranes tested MDAP∙CB8 and other fluorescent complexes as reporter pairs, providing us valuable information on the potential analytes that could be first implemented in the RT-PAMPA format (\u003Ca href=\"#B8\"\u003EBiedermann et al., 2020\u003C\u002Fa\u003E). To establish RT-PAMPA, we started with a small-scale analyte screening procedure, in order to eliminate false-negative results caused by the lack of response to the artificial receptor. These experiments could be performed in homogeneous solution, because only the fluorescence response of the receptor toward the analyte is being determined. A set of 29 analytes prepared in aqueous solution or with organic cosolvents has been examined for their response toward MDAP∙CB8. The fluorescence intensity changes upon addition of the analytes are visualized in \u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E. Most analytes caused a significant decrease of the fluorescence intensity, and changes >10% were considered to be sufficiently strong to be readily followed by RT-PAMPA, where a lower sensitivity was expected because of the temporal requirement of permeation. Indeed, the concentrations of the analytes in the fluorescence response experiments were conservatively set as 0.1 mmol\u002FL, below the test concentrations used in the subsequent RT-PAMPA (1 mmol\u002FL), such that already the permeation of a fraction of analyte from the donor to the acceptor well should ensure a fluorescence response in the upper.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g001.jpg\" alt=\"www.frontiersin.org\" id=\"F1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 1\u003C\u002Fstrong\u003E. Screening of the fluorescence response of the MDAP∙CB8 receptor upon addition of different analytes dissolved in water, 2% ethanol, and 2% DMSO, from top to bottom panels. The relative fluorescence intensity decrease upon addition of 20 equiv. of the corresponding analyte to 5 μmol\u002FL MDAP∙CB8 reporter pair solution is shown.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cp class=\"mb0 w100pc float_left mt15\"\u003EThe compounds that caused the largest fluorescence changes have several common structural features. MDAP possesses a positively charged conjugated organic moiety, which is predestined to get engaged in electrostatic interactions with electron-rich structures (e.g., indoles and coumarins). On the other hand, because of the size selectivity of the CB8 cavity with MDAP inside, large molecules and those with large branched residues showed no or weak associative binding (e.g., quinine, furosemide, primaquine, zolmitriptan, 1-adamantylamine, and 1-adamantanol). In general, an electron-rich, conjugated linear structure is preferred by the selected reporter pair. Naturally, because the sensing in RT-PAMPA is based on a molecular recognition process with an associated selectivity, the range of accessible analytes for a particular FAR is limited. Conversely, the technique is not limited to a single receptor. For example, berberine in combination with cucurbit[7]uril and lucigenin in a pair with \u003Ci\u003Ep\u003C\u002Fi\u003E-sulfonato-calix[4]arene are alternative reporter pairs, which respond to different classes of analytes, e.g., adamantyl and polycyclic aliphatic derivatives for the former (\u003Ca href=\"#B25\"\u003EMegyesi et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B26\"\u003EMoghaddam et al., 2011\u003C\u002Fa\u003E) and compounds with tethered trimethylammonium groups for the latter (\u003Ca href=\"#B1\"\u003EArena et al., 2004\u003C\u002Fa\u003E; \u003Ca href=\"#B19\"\u003EGuo et al., 2008\u003C\u002Fa\u003E, \u003Ca href=\"#B18\"\u003E2011\u003C\u002Fa\u003E). Through a combination of different receptors, the potential of RT-PAMPA can be expanded, although we concentrate herein on the demonstration for a single one, MDAP∙CB8.\u003C\u002Fp\u003E\n\u003Ch3\u003EInfluence of Cosolvent\u003C\u002Fh3\u003E\n\u003Cp class=\"mb15\"\u003EBuffers and organic cosolvents are widely used in traditional PAMPA to increase drug solubility in water. Pharmaceutical libraries routinely involve compound storage in dimethyl sulfoxide (DMSO), and compatibility with this cosolvent always needs to be ensured. Accordingly, we examined the influence of organic cosolvents, including water mixtures with DMSO, methanol, and ethanol. These control experiments were important, because the molecular-recognition process with synthetic macrocyclic cavities, such as that in CB8 or the MDAP∙CB8 complex, is frequently driven by hydrophobic interactions, which are being modulated in different solvents.\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe final concentration of the organic proportion ranged from 1 to 10% upon direct addition into the reporter pair solutions. As expected from a leveling of the hydrophobic driving force for receptor–analyte (host–guest) complexation in organic solvents, the fluorescence intensity decreased in all cases, and the effect became significant as the organic proportion increased (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E), with the largest drop (by 29%) being observed for 10% DMSO content. However, the response of the FAR was quite stable at low organic solvent proportion (1%), with the fluorescence intensity being reduced by only 5, 3, and 6% with methanol, ethanol, and DMSO, respectively. Although the results suggested that high proportions of organic cosolvent needed to be avoided, because they would reduce the sensitivity of the assay, the RT-PAMPA application should be sufficiently robust to allow common low DMSO proportions, and most importantly, the effect of organic cosolvents on the fluorescence response of the receptor was found to be predicable and systematic.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" name=\"figure2\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g002.jpg\" alt=\"www.frontiersin.org\" id=\"F2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 2\u003C\u002Fstrong\u003E. Fluorescence intensity change of the MDAP∙CB8 reporter pair solution upon addition of methanol, ethanol, or DMSO to the desired final concentration.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ch3\u003EInfluence of Lipid Layer\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EIn PAMPA, a lipid barrier needs to be crossed when an analyte moves from the donor plate into the acceptor plate. The initial PAMPA used egg lecithin as the lipid bilayer membrane (\u003Ca href=\"#B23\"\u003EKansy et al., 1998\u003C\u002Fa\u003E; \u003Ca href=\"#B11\"\u003EFaller, 2008\u003C\u002Fa\u003E); other options such as hexadecane (\u003Ca href=\"#B33\"\u003EWohnsland and Faller, 2001\u003C\u002Fa\u003E) and lipid mixtures (\u003Ca href=\"#B32\"\u003ESugano et al., 2001\u003C\u002Fa\u003E) have been developed subsequently. Herein, we selected a commercial Avanti lipid solution with good fluidity in all PAMPA experiments. As an alternative common lipid, 2% DOPC in dodecane solution has been used for comparison. Before proceeding to the RT-PAMPA experiments, we monitored the stability of the FAR in the acceptor well when in contact with the donor well in the absence of added analyte. Over a period of 7-h incubation time, a slight decrease of the fluorescence was monitored, which amounted to ca. 5 ± 2% for the 2% DOPC lipid and to 12 ± 3% for the Avanti premixed lipid (see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E). Presumably, this decrease reflects some dissolution of the receptor, or a component of it, in the lipid layer. Interestingly, this drop was independent, within error, of the presence of organic cosolvent (up to 20%) in the donor layer, which demonstrates that the diffusion of the polar organic cosolvents through the lipid does not contribute to the fluorescence changes in this time scale.\u003C\u002Fp\u003E\n\u003Ch3\u003ERT-PAMPA\u003C\u002Fh3\u003E\n\u003Cp class=\"mb0\"\u003EIn the actual RT-PAMPA experiments with MDAP∙CB8 and the Avanti lipid (\u003Ca href=\"#F3\"\u003EFigure 3A\u003C\u002Fa\u003E), the fluorescence decrease recorded from the different analytes needs to be compared with the fluorescence response in the absence of analyte, where also a slight decrease is observed (see previous section). Accordingly, significant fluorescence responses, indicative of analyte permeation through the lipid layer, were observed for umbelliferone, lansoprazole, \u003Csmall\u003EL\u003C\u002Fsmall\u003E-tryptophanamide, coumarin, propanil, thiabendazole, and indole. \u003Csmall\u003EL\u003C\u002Fsmall\u003E-Phenylalanine, serotonin, doxepin, and zolmitriptan showed no significant fluorescence response in comparison to the absence of analyte. Because these analytes show a strong fluorescence response in homogeneous solution (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E), they do not or too slowly permeate through the lipid layer in RT-PAMPA.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" name=\"figure3\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F597927\u002Ffchem-08-597927-HTML\u002Fimage_m\u002Ffchem-08-597927-g003.jpg\" alt=\"www.frontiersin.org\" id=\"F3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 3\u003C\u002Fstrong\u003E. RT-PAMPA with the MDAP∙CB8 fluorescent receptor and Avanti lipid films for monitoring the permeation process of \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E selected analytes that show binding to the fluorescent receptor and \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E indole at different analyte concentrations.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cp class=\"mb15 w100pc float_left mt15\"\u003EFor compounds that show insignificant fluorescence response\u002Fbinding toward the MDAP∙CB8 reporter pair, such as 1-adamantylamine or 1-adamantanol (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E), other reporter pairs can be in principle employed. To demonstrate, we conducted exploratory experiments (see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E) with the berberine∙cucurbit[7]uril reporter pair, which showed a strong fluorescence response, indicative of effective permeation, toward 1-adamantylamine and 1-adamantanol. The variability of the reporter pairs presents an additional asset of RT-PAMPA, which at the same time limits its general applicability for screening larger libraries with a single reporter pair. Among the tested reporter pairs, MDAP∙CB8 was, however, found to surpass the other candidates in terms of accessible analyte scope.\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EThe RT-PAMPA was carried out with two kinds of lipid membranes, the commercial Avanti PAMPA blend I and the laboratory prepared 2% DOPC dodecane solution (see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E for all results with 2% DOPC). A better resolution between the different analytes was observed with the commercial lipid layer, possibly because it is more permeable by dissolving 1% ethanol and stearic acid in dodecane besides just DOPC. The comparison also afforded differences in permeation profiles of some analytes. For example, umbelliferone, which showed an appreciable permeability through the Avanti lipid (\u003Ca href=\"#F3\"\u003EFigure 3A\u003C\u002Fa\u003E), did not permeate to a significant extent through the 2% DOPC lipid under RT-PAMPA conditions. As a particular advantage of RT-PAMPA, fast and slow permeation characteristics can be immediately differentiated from the permeation curves. Fast permeation is reflected by a sharp drop of the fluorescence during the initial several minutes, e.g., for coumarin, propanil, thiabendazole, and indole, revealing that a significant amount of the analyte has rapidly crossed the membrane model. In contrast, slowly permeating compounds such as umbelliferone, lansoprazole, and \u003Csmall\u003EL\u003C\u002Fsmall\u003E-tryptophanamide showed a fluorescence response on the time scale of several hours in RT-PAMPA. As expected, the kinetics of the permeation profiles (slow, moderate, and fast) nicely correlated with the known permeabilities of the analytes. For instance, the permeability coefficients (log\u003Ci\u003EP\u003C\u002Fi\u003E\u003Csub\u003Ee\u003C\u002Fsub\u003E) of indole and coumarin are reported as −4.50 and −4.55, respectively, which are considered fast (\u003Ca href=\"#B14\"\u003EFujikawa et al., 2007\u003C\u002Fa\u003E). In contrast, doxepin, whose permeability coefficient is < −6 in acidic solutions (which matches our experimental condition for using doxepin hydrochloride in the donor well), is categorized as slow permeation (\u003Ca href=\"#B29\"\u003EOja and Maran, 2015\u003C\u002Fa\u003E). Meanwhile, the performance of \u003Csmall\u003EL\u003C\u002Fsmall\u003E-tryptophanamide is moderate to slow with a permeability coefficient of −5.56 (\u003Ca href=\"#B14\"\u003EFujikawa et al., 2007\u003C\u002Fa\u003E). It should also be noted that simple (single-parameter) empirical correlations between the permeability coefficients and other physicochemical parameters of the analytes (such as their molecular size or their lipophilicity as assessed by octanol–water partition coefficients) do not apply, which emphasizes the need to experimentally determine the permeabilities of analytes with dedicated assays, such as RT-PAMPA (\u003Ca href=\"#B14\"\u003EFujikawa et al., 2007\u003C\u002Fa\u003E; \u003Ca href=\"#B8\"\u003EBiedermann et al., 2020\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003ERT-PAMPA is in principle also suitable to extract absolute permeation coefficients and rates, although these are strongly dependent on the actual experimental conditions (see above) and can only serve as a relative comparison and\u002For rough method-to-method comparison. The quantitative analysis requires that a plateau value for the final fluorescence intensity has been reached, which is indicative of analyte diffusion having reached equilibrium and\u002For complete consumption of the reporter pair. To differentiate between the two options, experiments at different analyte concentrations can be performed. For indole, see \u003Ca href=\"#F3\"\u003EFigure 3B\u003C\u002Fa\u003E; these experiments (from 0.01 to 1 mmol\u002FL) revealed variations of the plateau with varying indole concentration, which signifies that the diffusion equilibrium is actually being attained and that the artificial receptor is not being consumed; in the latter case, the same plateau would be reached with different rates. Under those conditions of equilibration and with the knowledge of the binding affinity between the analyte and the reporter pair, the absolute permeability coefficients of the analyte can be extracted (see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E). The effective permeability coefficient of indole (log \u003Ci\u003EP\u003C\u002Fi\u003E\u003Csub\u003Ee\u003C\u002Fsub\u003E) was calculated as −4.57 (as an average value), which compares favorably with that reported by others (log \u003Ci\u003EP\u003C\u002Fi\u003E\u003Csub\u003Ee\u003C\u002Fsub\u003E = −4.50, with 10% egg lecithin solution as the lipid barrier) (\u003Ca href=\"#B14\"\u003EFujikawa et al., 2007\u003C\u002Fa\u003E). A closer inspection of the permeability coefficients calculated for different time intervals or for different indole concentrations (see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E) shows small systematic trends (smaller values at higher analyte concentrations), which may be related to the almost complete consumption of the receptor at higher analyte concentrations and an associated larger error. Important to note, the presence of organic cosolvents in the donor well had a minor influence on the absolute permeation kinetics. To provide a specific example, we prepared 0.1 mmol\u002FL thiabendazole samples in both 2 and 20% ethanol, and the resulting permeation curves overlapped within the time of largest changes (initial hour, see \u003Ca href=\"#SM1\"\u003ESupplementary Material\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConclusions\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EIn summary, we have developed a real-time PAMPA model, referred to as RT-PAMPA, by introducing the FAR MDAP∙CB8 into the acceptor well. In contrast to the traditional single-point PAMPA, RT-PAMPA can offer multiple data point data along the entire incubation period, and it bypasses multiple incubation steps related to detection by UV-Vis absorption or measurement with LC\u002FMS. A rational protocol to perform the RT-PAMPA involves analyte screening as a preliminary test to evaluate the response of the fluorescent receptor to the analyte. For analytes that interact with the reporter pair, the complexation-induced fluorescence change in RT-PAMPA can be recorded in real time along during analyte incubation. Fast and slow permeation behavior can be readily recognized from the slope of the initial intensity drop. Absolute permeability coefficients of analytes can be obtained by knowledge of the binding affinity between analyte and the reporter pair. The method validation demonstrates that RT-PAMPA can be used robustly in aqueous solution and with organic cosolvents, including DMSO. Moreover, RT-PAMPA can be flexibly modified to monitor various analyte classes by changing to a suitable reporter pair. It is also possible to monitor permeation through different lipid compositions characteristic for different biological barriers.\u003C\u002Fp\u003E\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EData Availability Statement\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003C\u002Fp\u003E\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003ESH and WN designed the project and experiments. SH and AZ performed all PAMPA and screening experiments. AB-B performed the synthesis of MDAP. AH instructed preliminary experiments with valuable findings. SH and WN wrote the manuscript. All authors contributed to the article and approved the submitted version.\u003C\u002Fp\u003E\n\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFunding\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EThis work was supported by the Deutsche Forschungsgemeinschaft (DFG grants #NA-686\u002F11 for WN and #HE 5967\u002F4-1 for AH).\u003C\u002Fp\u003E\n\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe handling editor declared a past collaboration with the authors AH and WN.\u003C\u002Fp\u003E\n\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EThe authors thank Solène Collin and Nader Al Danaf for preliminary experiments and Dr. Frank Biedermann for encouraging the use of the MDAP∙CB8 receptor.\u003C\u002Fp\u003E\n\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ESupplementary Material\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\" id=\"SM1\"\u003EThe Supplementary Material for this article can be found online at: \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffchem.2020.597927\u002Ffull#supplementary-material\"\u003Ehttps:\u002F\u002Fwww.frontiersin.org\u002Farticles\u002F10.3389\u002Ffchem.2020.597927\u002Ffull#supplementary-material\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003Ca id=\"h12\" name=\"h12\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E Arena, G., Gentile, S., Gulino, F. G., Sciotto, D., and Sgarlata, C. (2004). Water-soluble pentasulfonatocalix[5]arene: selective recognition of ditopic trimethylammonium cations by a triple non-covalent interaction. \u003Ci\u003ETetrahedron Lett.\u003C\u002Fi\u003E 45, 7091–7094. doi: 10.1016\u002Fj.tetlet.2004.07.108\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.tetlet.2004.07.108\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=G.+Arena&author=S.+Gentile&author=F.+G.+Gulino&author=D.+Sciotto&author=C.+Sgarlata+&publication_year=2004&title=Water-soluble+pentasulfonatocalix[5]arene%3A+selective+recognition+of+ditopic+trimethylammonium+cations+by+a+triple+non-covalent+interaction&journal=Tetrahedron+Lett.&volume=45&pages=7091-7094\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B2\" id=\"B2\"\u003E\u003C\u002Fa\u003E Artursson, P., Palm, K., and Luthman, K. (2001). Caco-2 monolayers in experimental and theoretical predictions of drug transport. \u003Ci\u003EAdv. Drug Deliv. Rev.\u003C\u002Fi\u003E 46, 27–43. doi: 10.1016\u002FS0169-409X(00)00128-9\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F11259831\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002FS0169-409X(00)00128-9\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=P.+Artursson&author=K.+Palm&author=K.+Luthman+&publication_year=2001&title=Caco-2+monolayers+in+experimental+and+theoretical+predictions+of+drug+transport&journal=Adv.+Drug+Deliv.+Rev.&volume=46&pages=27-43\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B3\" id=\"B3\"\u003E\u003C\u002Fa\u003E Assaf, K. I., Begaj, B., Frank, A., Nilam, M., Mougharbel, A. S., Kortz, U., et al. (2019). High-affinity binding of metallacarborane cobalt bis(dicarbollide) anions to cyclodextrins and application to membrane translocation. \u003Ci\u003EJ. Org. Chem.\u003C\u002Fi\u003E 84, 11790–11798. doi: 10.1021\u002Facs.joc.9b01688\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F31274306\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Facs.joc.9b01688\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=K.+I.+Assaf&author=B.+Begaj&author=A.+Frank&author=M.+Nilam&author=A.+S.+Mougharbel&author=U.+Kortz+&publication_year=2019&title=High-affinity+binding+of+metallacarborane+cobalt+bis(dicarbollide)+anions+to+cyclodextrins+and+application+to+membrane+translocation&journal=J.+Org.+Chem.&volume=84&pages=11790-11798\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B4\" id=\"B4\"\u003E\u003C\u002Fa\u003E Avdeef, A. (2003). \u003Ci\u003EAbsorption and Drug Development\u003C\u002Fi\u003E. New York, NY: John Wiley & Sons, Inc.\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=A.+Avdeef+&publication_year=2003&title=Absorption+and+Drug+Development\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B5\" id=\"B5\"\u003E\u003C\u002Fa\u003E Avdeef, A., Ruiz, A., Nalda, R., Ruell, J. A., Tsinman, O., Gonzalez, I., et al. (2004). PAMPA - a drug absorption in vitro model: 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. \u003Ci\u003EEur. J. Pharm. Sci.\u003C\u002Fi\u003E 21, 429–441. doi: 10.1016\u002Fj.ejps.2003.10.009\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F14998573\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejps.2003.10.009\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=A.+Avdeef&author=A.+Ruiz&author=R.+Nalda&author=J.+A.+Ruell&author=O.+Tsinman&author=I.+Gonzalez+&publication_year=2004&title=PAMPA+-+a+drug+absorption+in+vitro+model%3A+7.+Comparing+rat+in+situ,+Caco-2,+and+PAMPA+permeability+of+fluoroquinolones&journal=Eur.+J.+Pharm.+Sci.&volume=21&pages=429-441\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B6\" id=\"B6\"\u003E\u003C\u002Fa\u003E Barba-Bon, A., Pan, Y.-C., Biedermann, F., Guo, D. -S., Nau, W. M., and Hennig, A. (2019). Fluorescence monitoring of peptide transport pathways into large and giant vesicles by supramolecular host-dye pairs. \u003Ci\u003EJ. Am. Chem. Soc.\u003C\u002Fi\u003E 141, 20137–20145. doi: 10.1021\u002Fjacs.9b09563\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F31739668\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fjacs.9b09563\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=A.+Barba-Bon&author=Y.+-C.+Pan&author=F.+Biedermann&author=D.++-S.+Guo&author=W.+M.+Nau&author=A.+Hennig+&publication_year=2019&title=Fluorescence+monitoring+of+peptide+transport+pathways+into+large+and+giant+vesicles+by+supramolecular+host-dye+pairs&journal=J.+Am.+Chem.+Soc.&volume=141&pages=20137-20145\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B7\" id=\"B7\"\u003E\u003C\u002Fa\u003E Berben, P., Bauer-Brandl, A., Brandl, M., Faller, B., Flaten, G., Jacobsen, A., et al. (2018). Drug permeability profiling using cell-free permeation tools: overview and applications. \u003Ci\u003EEur. J. Pharm. Sci.\u003C\u002Fi\u003E 119, 219–233. doi: 10.1016\u002Fj.ejps.2018.04.016\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F29660464\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejps.2018.04.016\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=P.+Berben&author=A.+Bauer-Brandl&author=M.+Brandl&author=B.+Faller&author=G.+Flaten&author=A.+Jacobsen+&publication_year=2018&title=Drug+permeability+profiling+using+cell-free+permeation+tools%3A+overview+and+applications&journal=Eur.+J.+Pharm.+Sci.&volume=119&pages=219-233\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B8\" id=\"B8\"\u003E\u003C\u002Fa\u003E Biedermann, F., Ghale, G., Hennig, A., and Nau, W. M. (2020). Fluorescent artificial receptor-based membrane assay (FARMA) for spatiotemporally resolved monitoring of biomembrane permeability. \u003Ci\u003ECommun. Biol.\u003C\u002Fi\u003E 3:383. doi: 10.1038\u002Fs42003-020-1108-9\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F32669621\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs42003-020-1108-9\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=F.+Biedermann&author=G.+Ghale&author=A.+Hennig&author=W.+M.+Nau+&publication_year=2020&title=Fluorescent+artificial+receptor-based+membrane+assay+(FARMA)+for+spatiotemporally+resolved+monitoring+of+biomembrane+permeability&journal=Commun.+Biol.&volume=3&pages=383\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B9\" id=\"B9\"\u003E\u003C\u002Fa\u003E Biedermann, F., Hathazi, D., and Nau, W. M. (2015). Associative chemosensing by fluorescent macrocycle-dye complexes - a versatile enzyme assay platform beyond indicator displacement. \u003Ci\u003EChem. Commun.\u003C\u002Fi\u003E 51, 4977–4980. doi: 10.1039\u002FC4CC10227D\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F25622263\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1039\u002FC4CC10227D\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=F.+Biedermann&author=D.+Hathazi&author=W.+M.+Nau+&publication_year=2015&title=Associative+chemosensing+by+fluorescent+macrocycle-dye+complexes+-+a+versatile+enzyme+assay+platform+beyond+indicator+displacement&journal=Chem.+Commun.&volume=51&pages=4977-4980\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B10\" id=\"B10\"\u003E\u003C\u002Fa\u003E Cejas, M. A., and Raymo, F. M. (2005). Fluorescent diazapyrenium films and their response to dopamine. \u003Ci\u003ELangmuir.\u003C\u002Fi\u003E 21, 5795–5802. doi: 10.1021\u002Fla0502793\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F15952825\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fla0502793\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+A.+Cejas&author=F.+M.+Raymo+&publication_year=2005&title=Fluorescent+diazapyrenium+films+and+their+response+to+dopamine&journal=Langmuir.&volume=21&pages=5795-5802\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B11\" id=\"B11\"\u003E\u003C\u002Fa\u003E Faller, B. (2008). Artificial membrane assays to assess permeability. \u003Ci\u003ECurr. Drug Metab.\u003C\u002Fi\u003E 9, 886–892. doi: 10.2174\u002F138920008786485227\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F18991585\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.2174\u002F138920008786485227\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=B.+Faller+&publication_year=2008&title=Artificial+membrane+assays+to+assess+permeability&journal=Curr.+Drug+Metab.&volume=9&pages=886-892\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B12\" id=\"B12\"\u003E\u003C\u002Fa\u003E Florea, M., Kudithipudi, S., Rei, A., González-Álvarez, M. J., Jeltsch, A., and Nau, W. M. (2012). A fluorescence-based supramolecular tandem assay for monitoring lysine methyltransferase activity in homogeneous solution. \u003Ci\u003EChem. Eur. J.\u003C\u002Fi\u003E 18, 3521–3528. doi: 10.1002\u002Fchem.201103397\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F22367964\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fchem.201103397\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Florea&author=S.+Kudithipudi&author=A.+Rei&author=M.+J.+González-Álvarez&author=A.+Jeltsch&author=W.+M.+Nau+&publication_year=2012&title=A+fluorescence-based+supramolecular+tandem+assay+for+monitoring+lysine+methyltransferase+activity+in+homogeneous+solution&journal=Chem.+Eur.+J.&volume=18&pages=3521-3528\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B13\" id=\"B13\"\u003E\u003C\u002Fa\u003E Florea, M., and Nau, W. M. (2011). Strong binding of hydrocarbons to cucurbituril probed by fluorescent dye displacement: a supramolecular gas-sensing ensemble. \u003Ci\u003EAngew. Chem. Int. Ed.\u003C\u002Fi\u003E 50, 9338–9342. doi: 10.1002\u002Fanie.201104119\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F21948429\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fanie.201104119\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Florea&author=W.+M.+Nau+&publication_year=2011&title=Strong+binding+of+hydrocarbons+to+cucurbituril+probed+by+fluorescent+dye+displacement%3A+a+supramolecular+gas-sensing+ensemble&journal=Angew.+Chem.+Int.+Ed.&volume=50&pages=9338-9342\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B14\" id=\"B14\"\u003E\u003C\u002Fa\u003E Fujikawa, M., Nakao, K., Shimizu, R., and Akamatsu, M. (2007). QSAR study on permeability of hydrophobic compounds with artificial membranes. \u003Ci\u003EBioorg. Med. Chem.\u003C\u002Fi\u003E 15, 3756–3767. doi: 10.1016\u002Fj.bmc.2007.03.040\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F17418579\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.bmc.2007.03.040\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Fujikawa&author=K.+Nakao&author=R.+Shimizu&author=M.+Akamatsu+&publication_year=2007&title=QSAR+study+on+permeability+of+hydrophobic+compounds+with+artificial+membranes&journal=Bioorg.+Med.+Chem.&volume=15&pages=3756-3767\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B15\" id=\"B15\"\u003E\u003C\u002Fa\u003E Ghale, G., Lanctôt, A. G., Kreissl, H. T., Jacob, M. H., Weingart, H., Winterhalter, M., et al. (2014). Chemosensing ensembles for monitoring biomembrane transport in real time. \u003Ci\u003EAngew. Chem. Int. Ed.\u003C\u002Fi\u003E 53, 2762–2765. doi: 10.1002\u002Fanie.201309583\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F24469927\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fanie.201309583\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=G.+Ghale&author=A.+G.+Lanctôt&author=H.+T.+Kreissl&author=M.+H.+Jacob&author=H.+Weingart&author=M.+Winterhalter+&publication_year=2014&title=Chemosensing+ensembles+for+monitoring+biomembrane+transport+in+real+time&journal=Angew.+Chem.+Int.+Ed.&volume=53&pages=2762-2765\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B16\" id=\"B16\"\u003E\u003C\u002Fa\u003E Ghale, G., and Nau, W. M. (2014). Dynamically analyte-responsive macrocyclic host-fluorophore systems. \u003Ci\u003EAcc. Chem. Res.\u003C\u002Fi\u003E 47, 2150–2159. doi: 10.1021\u002Far500116d\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F24785659\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Far500116d\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=G.+Ghale&author=W.+M.+Nau+&publication_year=2014&title=Dynamically+analyte-responsive+macrocyclic+host-fluorophore+systems&journal=Acc.+Chem.+Res.&volume=47&pages=2150-2159\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B17\" id=\"B17\"\u003E\u003C\u002Fa\u003E Ghale, G., Ramalingam, V., Urbach, A. R., and Nau, W. M. (2011). Determining protease substrate selectivity and inhibition by label-free supramolecular tandem enzyme assays. \u003Ci\u003EJ. Am. Chem. Soc.\u003C\u002Fi\u003E 133, 7528–7535. doi: 10.1021\u002Fja2013467\n\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fja2013467\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=G.+Ghale&author=V.+Ramalingam&author=A.+R.+Urbach&author=W.+M.+Nau+&publication_year=2011&title=Determining+protease+substrate+selectivity+and+inhibition+by+label-free+supramolecular+tandem+enzyme+assays&journal=J.+Am.+Chem.+Soc.&volume=133&pages=7528-7535\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B18\" id=\"B18\"\u003E\u003C\u002Fa\u003E Guo, D. -S., Uzunova, V. D., Su, X., Liu, Y., and Nau, W. M. (2011). Operational calixarene-based fluorescent sensing systems for choline and acetylcholine and their application to enzymatic reactions. \u003Ci\u003EChem. Sci.\u003C\u002Fi\u003E 2, 1722–1734. doi: 10.1039\u002Fc1sc00231g\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1039\u002Fc1sc00231g\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=D.++-S.+Guo&author=V.+D.+Uzunova&author=X.+Su&author=Y.+Liu&author=W.+M.+Nau+&publication_year=2011&title=Operational+calixarene-based+fluorescent+sensing+systems+for+choline+and+acetylcholine+and+their+application+to+enzymatic+reactions&journal=Chem.+Sci.&volume=2&pages=1722-1734\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B19\" id=\"B19\"\u003E\u003C\u002Fa\u003E Guo, D. -S., Wang, K., and Liu, Y. (2008). Selective binding behaviors of p-sulfonatocalixarenes in aqueous solution. \u003Ci\u003EJ. Incl. Phenom. Macrocycl. Chem\u003C\u002Fi\u003E. 62, 1–21. doi: 10.1007\u002Fs10847-008-9452-2\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs10847-008-9452-2\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=D.++-S.+Guo&author=K.+Wang&author=Y.+Liu+&publication_year=2008&title=Selective+binding+behaviors+of+p-sulfonatocalixarenes+in+aqueous+solution&journal=J.+Incl.+Phenom.+Macrocycl.+Chem&volume=62&pages=1-21\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B20\" id=\"B20\"\u003E\u003C\u002Fa\u003E Hanlan, L., Chantel, S., Guy, C., Chao, D., Avdeef, A., and Tischler, M. (2003). In vitro permeability of poorly aqueous soluble compounds using different solubilizers in the PAMPA assay with liquid chromatography\u002Fmass spectrometry detection. \u003Ci\u003EPharm Res.\u003C\u002Fi\u003E 20, 1820–1826. doi: 10.1023\u002FB:PHAM.0000003380.44755.5a\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1023\u002FB:PHAM.0000003380.44755.5a\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=L.+Hanlan&author=S.+Chantel&author=C.+Guy&author=D.+Chao&author=A.+Avdeef&author=M.+Tischler+&publication_year=2003&title=In+vitro+permeability+of+poorly+aqueous+soluble+compounds+using+different+solubilizers+in+the+PAMPA+assay+with+liquid+chromatography%2Fmass+spectrometry+detection&journal=Pharm+Res.&volume=20&pages=1820-1826\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B21\" id=\"B21\"\u003E\u003C\u002Fa\u003E Hayeshi, R., Hilgendorf, C., Artursson, P., Augustijns, P., Brodin, B., Dehertogh, P., et al. (2008). Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories. \u003Ci\u003EEur. J. Pharm. Sci.\u003C\u002Fi\u003E 35, 383–396. doi: 10.1016\u002Fj.ejps.2008.08.004\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F18782614\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejps.2008.08.004\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=R.+Hayeshi&author=C.+Hilgendorf&author=P.+Artursson&author=P.+Augustijns&author=B.+Brodin&author=P.+Dehertogh+&publication_year=2008&title=Comparison+of+drug+transporter+gene+expression+and+functionality+in+Caco-2+cells+from+10+different+laboratories&journal=Eur.+J.+Pharm.+Sci.&volume=35&pages=383-396\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B22\" id=\"B22\"\u003E\u003C\u002Fa\u003E Hou, T. J., Zhang, W., Xia, K., Qiao, X. B., and Xu, X. J. (2004). ADME evaluation in drug discovery. 5. correlation of Caco-2 permeation with simple molecular properties. \u003Ci\u003EJ. Chem. Inf. Comput. Sci.\u003C\u002Fi\u003E 44, 1585–1600. doi: 10.1021\u002Fci049884m\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F15446816\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fci049884m\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=T.+J.+Hou&author=W.+Zhang&author=K.+Xia&author=X.+B.+Qiao&author=X.+J.+Xu+&publication_year=2004&title=ADME+evaluation+in+drug+discovery.+5.+correlation+of+Caco-2+permeation+with+simple+molecular+properties&journal=J.+Chem.+Inf.+Comput.+Sci.&volume=44&pages=1585-1600\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B23\" id=\"B23\"\u003E\u003C\u002Fa\u003E Kansy, M., Senner, F., and Gubernator, K. (1998). Physicochemical high throughput screening: parallel artificial membrane permeability assay in the description of passive absorption processes. \u003Ci\u003EJ. Med. Chem.\u003C\u002Fi\u003E 41, 1070–1110. doi: 10.1021\u002Fjm970530e\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F9544199\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fjm970530e\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Kansy&author=F.+Senner&author=K.+Gubernator+&publication_year=1998&title=Physicochemical+high+throughput+screening%3A+parallel+artificial+membrane+permeability+assay+in+the+description+of+passive+absorption+processes&journal=J.+Med.+Chem.&volume=41&pages=1070-1110\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B24\" id=\"B24\"\u003E\u003C\u002Fa\u003E Márquez, C., Fang, H., and Nau, W. M. (2004). Cucurbiturils: molecular nanocapsules for time-resolved fluorescence-based assays. \u003Ci\u003EIEEE Trans. NanoBiosci.\u003C\u002Fi\u003E 3, 39–45. doi: 10.1109\u002FTNB.2004.824269\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F15382642\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1109\u002FTNB.2004.824269\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=C.+Márquez&author=H.+Fang&author=W.+M.+Nau+&publication_year=2004&title=Cucurbiturils%3A+molecular+nanocapsules+for+time-resolved+fluorescence-based+assays&journal=IEEE+Trans.+NanoBiosci.&volume=3&pages=39-45\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B25\" id=\"B25\"\u003E\u003C\u002Fa\u003E Megyesi, M., Biczók, L., and Jablonkai, I. (2008). Highly sensitive fluorescence response to inclusion complex formation of berberine alkaloid with cucurbit[7]uril. \u003Ci\u003EJ. Phys. Chem. C.\u003C\u002Fi\u003E 112, 3410–3416. doi: 10.1021\u002Fjp075348w\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fjp075348w\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Megyesi&author=L.+Biczók&author=I.+Jablonkai+&publication_year=2008&title=Highly+sensitive+fluorescence+response+to+inclusion+complex+formation+of+berberine+alkaloid+with+cucurbit[7]uril&journal=J.+Phys.+Chem.+C.&volume=112&pages=3410-3416\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B26\" id=\"B26\"\u003E\u003C\u002Fa\u003E Moghaddam, S., Yang, C., Rekharsky, M., Ko, Y. H., Kim, K., Inoue, Y., et al. (2011). New ultrahigh affinity host-guest complexes of cucurbit[7]uril with bicyclo[2.2.2]octane and adamantane guests: thermodynamic analysis and evaluation of M2 affinity calculations. \u003Ci\u003EJ. Am. Chem. Soc.\u003C\u002Fi\u003E 133, 3570–3581. doi: 10.1021\u002Fja109904u\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F21341773\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fja109904u\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=S.+Moghaddam&author=C.+Yang&author=M.+Rekharsky&author=Y.+H.+Ko&author=K.+Kim&author=Y.+Inoue+&publication_year=2011&title=New+ultrahigh+affinity+host-guest+complexes+of+cucurbit[7]uril+with+bicyclo[2.2.2]octane+and+adamantane+guests%3A+thermodynamic+analysis+and+evaluation+of+M2+affinity+calculations&journal=J.+Am.+Chem.+Soc.&volume=133&pages=3570-3581\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B27\" id=\"B27\"\u003E\u003C\u002Fa\u003E Nielsen, P. E., and Avdeef, A. (2004). PAMPA-a drug absorption in vitro model 8. Apparent filter porosity and the unstirred water layer. \u003Ci\u003EEur. J. Pharm. Sci.\u003C\u002Fi\u003E 22, 33–41. doi: 10.1016\u002Fj.ejps.2004.02.003\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F15113581\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejps.2004.02.003\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=P.+E.+Nielsen&author=A.+Avdeef+&publication_year=2004&title=PAMPA-a+drug+absorption+in+vitro+model+8.+Apparent+filter+porosity+and+the+unstirred+water+layer&journal=Eur.+J.+Pharm.+Sci.&volume=22&pages=33-41\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B28\" id=\"B28\"\u003E\u003C\u002Fa\u003E Norouzy, A., Azizi, Z., and Nau, W. M. (2015). Indicator displacement assays inside live cells. \u003Ci\u003EAngew. Chem. Int. Ed.\u003C\u002Fi\u003E 54, 792–795. doi: 10.1002\u002Fanie.201407808\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F25430503\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fanie.201407808\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=A.+Norouzy&author=Z.+Azizi&author=W.+M.+Nau+&publication_year=2015&title=Indicator+displacement+assays+inside+live+cells&journal=Angew.+Chem.+Int.+Ed.&volume=54&pages=792-795\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B29\" id=\"B29\"\u003E\u003C\u002Fa\u003E Oja, M., and Maran, U. (2015). Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds. \u003Ci\u003ESAR QSAR Environ. Res.\u003C\u002Fi\u003E 26, 701–719. doi: 10.1080\u002F1062936X.2015.1085896\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F26383235\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1080\u002F1062936X.2015.1085896\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=M.+Oja&author=U.+Maran+&publication_year=2015&title=Quantitative+structure-permeability+relationships+at+various+pH+values+for+acidic+and+basic+drugs+and+drug-like+compounds&journal=SAR+QSAR+Environ.+Res.&volume=26&pages=701-719\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B30\" id=\"B30\"\u003E\u003C\u002Fa\u003E Sindelar, V., Cejas, M. A., Raymo, F. M., Chen, W., Parker, S. E., and Kaifer, A. E. (2005). Supramolecular assembly of 2,7-dimethyldiazapyrenium and cucurbit[8]uril: a new fluorescent host for detection of catechol and dopamine. \u003Ci\u003EChem. Eur. J.\u003C\u002Fi\u003E 11, 7054–7059. doi: 10.1002\u002Fchem.200500917\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F16175642\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fchem.200500917\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=V.+Sindelar&author=M.+A.+Cejas&author=F.+M.+Raymo&author=W.+Chen&author=S.+E.+Parker&author=A.+E.+Kaifer+&publication_year=2005&title=Supramolecular+assembly+of+2,7-dimethyldiazapyrenium+and+cucurbit[8]uril%3A+a+new+fluorescent+host+for+detection+of+catechol+and+dopamine&journal=Chem.+Eur.+J.&volume=11&pages=7054-7059\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B31\" id=\"B31\"\u003E\u003C\u002Fa\u003E Sinn, S., and Biedermann, F. (2018). Chemical sensors based on cucurbit[n]uril macrocycles. \u003Ci\u003EIsr. J. Chem.\u003C\u002Fi\u003E 58, 357–412. doi: 10.1002\u002Fijch.201700118\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1002\u002Fijch.201700118\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=S.+Sinn&author=F.+Biedermann+&publication_year=2018&title=Chemical+sensors+based+on+cucurbit[n]uril+macrocycles&journal=Isr.+J.+Chem.&volume=58&pages=357-412\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B32\" id=\"B32\"\u003E\u003C\u002Fa\u003E Sugano, K., Hamada, H., Machida, M., and Ushio, H. (2001). High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeability assay. \u003Ci\u003EJ. Biomolec. Screen.\u003C\u002Fi\u003E 6, 189–196. doi: 10.1177\u002F108705710100600309\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F11689115\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1177\u002F108705710100600309\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=K.+Sugano&author=H.+Hamada&author=M.+Machida&author=H.+Ushio+&publication_year=2001&title=High+throughput+prediction+of+oral+absorption%3A+improvement+of+the+composition+of+the+lipid+solution+used+in+parallel+artificial+membrane+permeability+assay&journal=J.+Biomolec.+Screen.&volume=6&pages=189-196\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"References\"\u003E\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B33\" id=\"B33\"\u003E\u003C\u002Fa\u003E Wohnsland, F., and Faller, B. (2001). High-throughput permeability pH profile and high-throughput alkane\u002Fwater log \u003Ci\u003EP\u003C\u002Fi\u003E with artificial membranes. \u003Ci\u003EJ. Med. Chem.\u003C\u002Fi\u003E 44, 923–930. doi: 10.1021\u002Fjm001020e\u003C\u002Fp\u003E\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F11300874\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1021\u002Fjm001020e\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=F.+Wohnsland&author=B.+Faller+&publication_year=2001&title=High-throughput+permeability+pH+profile+and+high-throughput+alkane%2Fwater+log+P+with+artificial+membranes&journal=J.+Med.+Chem.&volume=44&pages=923-930\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"AbstractSummary\"\u003E\n\u003Cp\u003E\u003Cspan\u003EKeywords:\u003C\u002Fspan\u003E drug discovery, permeability, fluorescence, cucurbituril, passive diffusion\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E He S, Zhiti A, Barba-Bon A, Hennig A and Nau WM (2020) Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors. \u003Ci\u003EFront. Chem.\u003C\u002Fi\u003E 8:597927. doi: 10.3389\u002Ffchem.2020.597927\u003C\u002Fp\u003E\n\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 22 August 2020; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 06 October 2020;\u003Cbr\u003E \u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 03 November 2020.\u003C\u002Fp\u003E\n\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F695885\u002Foverview\"\u003EChusen Huang\u003C\u002Fa\u003E, Shanghai Normal University, China\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F924033\u002Foverview\"\u003EHaibo Zhang\u003C\u002Fa\u003E, Wuhan University, China\u003Cbr\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F645119\u002Foverview\"\u003EAdam Charles Sedgwick\u003C\u002Fa\u003E, University of Texas at Austin, United States\u003C\u002Fdiv\u003E\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2020 He, Zhiti, Barba-Bon, Hennig and Nau. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Suhang He, \u003Ca id=\"encmail\"\u003Ecy5oZUBqYWNvYnMtdW5pdmVyc2l0eS5kZQ==\u003C\u002Fa\u003E; Werner M. Nau, \u003Ca id=\"encmail\"\u003Edy5uYXVAamFjb2JzLXVuaXZlcnNpdHkuZGU=\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EMaterials and Methods\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003EResults and Discussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EConclusions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EData Availability Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h8\"\u003EFunding\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h9\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h10\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h11\"\u003ESupplementary Material\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h12\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E"},files:[{name:"EPUB.epub",fileServerPackageEntryId:g,type:{code:ay,name:ay}},{name:az,fileServerPackageEntryId:"fchem-08-597927\u002Ffchem-08-597927.pdf",type:{code:o,name:o}},{name:az,fileServerPackageEntryId:g,type:{code:o,name:o}},{name:"fchem-08-597927.xml",fileServerPackageEntryId:"fchem-08-597927\u002Ffchem-08-597927.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional 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In a second step, the samples of each well are transferred to a UV-Vis–compatible microplate and optically measured (applicable only to analytes with sufficient absorbance) or sampled by mass-spectrometric analysis. The required incubation period, sample transfer, and detection methods jointly limit the scalability of PAMPA to high-throughput screening format. We introduce a modification of the PAMPA method that allows direct fluorescence detection, without sample transfer, in real time (RT-PAMPA). The method employs the use of a fluorescent artificial receptor (FAR), composed of a macrocycle in combination with an encapsulated fluorescent dye, administered in the acceptor chamber of conventional PAMPA microplates. Because the detection principle relies on the molecular recognition of an analyte by the receptor and the associated fluorescence response, concentration changes of any analyte that binds to the receptor can be monitored (molecules with aromatic residues in the present example), regardless of the spectroscopic properties of the analyte itself. Moreover, because the fluorescence of the (upper) acceptor well can be read out directly by fluorescence in a microplate reader, the permeation of the drug through the planar lipid layer can be monitored in real time. 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