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Plasma protein binding - Wikipedia
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id="vector-page-titlebar-toc-unpinned-container" class="vector-unpinned-container"> </div> </div> </div> </nav> <h1 id="firstHeading" class="firstHeading mw-first-heading"><span class="mw-page-title-main">Plasma protein binding</span></h1> <div id="p-lang-btn" class="vector-dropdown mw-portlet mw-portlet-lang" > <input type="checkbox" id="p-lang-btn-checkbox" role="button" aria-haspopup="true" data-event-name="ui.dropdown-p-lang-btn" class="vector-dropdown-checkbox mw-interlanguage-selector" aria-label="Go to an article in another language. Available in 20 languages" > <label id="p-lang-btn-label" for="p-lang-btn-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--action-progressive mw-portlet-lang-heading-20" aria-hidden="true" ><span class="vector-icon mw-ui-icon-language-progressive mw-ui-icon-wikimedia-language-progressive"></span> <span class="vector-dropdown-label-text">20 languages</span> </label> <div class="vector-dropdown-content"> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li class="interlanguage-link interwiki-ar mw-list-item"><a href="https://ar.wikipedia.org/wiki/%D8%B1%D8%A8%D8%B7_%D8%A8%D8%B1%D9%88%D8%AA%D9%8A%D9%86%D9%8A" title="ربط بروتيني – Arabic" lang="ar" hreflang="ar" data-title="ربط بروتيني" data-language-autonym="العربية" data-language-local-name="Arabic" class="interlanguage-link-target"><span>العربية</span></a></li><li class="interlanguage-link interwiki-ca mw-list-item"><a href="https://ca.wikipedia.org/wiki/Uni%C3%B3_a_prote%C3%AFnes_plasm%C3%A0tiques" title="Unió a proteïnes plasmàtiques – Catalan" lang="ca" hreflang="ca" data-title="Unió a proteïnes plasmàtiques" data-language-autonym="Català" data-language-local-name="Catalan" class="interlanguage-link-target"><span>Català</span></a></li><li class="interlanguage-link interwiki-de mw-list-item"><a href="https://de.wikipedia.org/wiki/Proteinbindung" title="Proteinbindung – German" lang="de" hreflang="de" data-title="Proteinbindung" data-language-autonym="Deutsch" data-language-local-name="German" class="interlanguage-link-target"><span>Deutsch</span></a></li><li class="interlanguage-link interwiki-es mw-list-item"><a href="https://es.wikipedia.org/wiki/Uni%C3%B3n_a_prote%C3%ADna_plasm%C3%A1tica" title="Unión a proteína plasmática – Spanish" lang="es" hreflang="es" data-title="Unión a proteína plasmática" data-language-autonym="Español" data-language-local-name="Spanish" class="interlanguage-link-target"><span>Español</span></a></li><li class="interlanguage-link interwiki-fa mw-list-item"><a href="https://fa.wikipedia.org/wiki/%D9%BE%DB%8C%D9%88%D9%86%D8%AF_%D9%BE%D8%B1%D9%88%D8%AA%D8%A6%DB%8C%D9%86%DB%8C" title="پیوند پروتئینی – Persian" lang="fa" hreflang="fa" data-title="پیوند پروتئینی" data-language-autonym="فارسی" data-language-local-name="Persian" class="interlanguage-link-target"><span>فارسی</span></a></li><li class="interlanguage-link interwiki-id mw-list-item"><a href="https://id.wikipedia.org/wiki/Ikatan_protein_plasma" title="Ikatan protein plasma – Indonesian" lang="id" hreflang="id" data-title="Ikatan protein plasma" data-language-autonym="Bahasa Indonesia" data-language-local-name="Indonesian" class="interlanguage-link-target"><span>Bahasa Indonesia</span></a></li><li class="interlanguage-link interwiki-it mw-list-item"><a href="https://it.wikipedia.org/wiki/Legame_dei_farmaci_alle_proteine_plasmatiche" title="Legame dei farmaci alle proteine plasmatiche – Italian" lang="it" hreflang="it" data-title="Legame dei farmaci alle proteine plasmatiche" data-language-autonym="Italiano" data-language-local-name="Italian" class="interlanguage-link-target"><span>Italiano</span></a></li><li class="interlanguage-link interwiki-mr mw-list-item"><a href="https://mr.wikipedia.org/wiki/%E0%A4%AA%E0%A5%8D%E0%A4%B0%E0%A4%A5%E0%A4%BF%E0%A4%A8%E0%A4%AC%E0%A4%82%E0%A4%A7%E0%A4%A4%E0%A4%BE" title="प्रथिनबंधता – Marathi" lang="mr" hreflang="mr" data-title="प्रथिनबंधता" data-language-autonym="मराठी" data-language-local-name="Marathi" class="interlanguage-link-target"><span>मराठी</span></a></li><li class="interlanguage-link interwiki-ms mw-list-item"><a href="https://ms.wikipedia.org/wiki/Pengikatan_protein_plasma" title="Pengikatan protein plasma – Malay" lang="ms" hreflang="ms" data-title="Pengikatan protein plasma" data-language-autonym="Bahasa Melayu" data-language-local-name="Malay" class="interlanguage-link-target"><span>Bahasa Melayu</span></a></li><li class="interlanguage-link interwiki-nl mw-list-item"><a href="https://nl.wikipedia.org/wiki/Plasma-eiwitbinding" title="Plasma-eiwitbinding – Dutch" lang="nl" hreflang="nl" data-title="Plasma-eiwitbinding" data-language-autonym="Nederlands" data-language-local-name="Dutch" class="interlanguage-link-target"><span>Nederlands</span></a></li><li class="interlanguage-link interwiki-ja mw-list-item"><a href="https://ja.wikipedia.org/wiki/%E8%A1%80%E6%BC%BF%E3%82%BF%E3%83%B3%E3%83%91%E3%82%AF%E7%B5%90%E5%90%88" title="血漿タンパク結合 – Japanese" lang="ja" hreflang="ja" data-title="血漿タンパク結合" data-language-autonym="日本語" data-language-local-name="Japanese" class="interlanguage-link-target"><span>日本語</span></a></li><li class="interlanguage-link interwiki-pt mw-list-item"><a href="https://pt.wikipedia.org/wiki/Liga%C3%A7%C3%A3o_a_prote%C3%ADnas_plasm%C3%A1ticas" title="Ligação a proteínas plasmáticas – Portuguese" lang="pt" hreflang="pt" data-title="Ligação a proteínas plasmáticas" data-language-autonym="Português" data-language-local-name="Portuguese" class="interlanguage-link-target"><span>Português</span></a></li><li class="interlanguage-link interwiki-ru mw-list-item"><a href="https://ru.wikipedia.org/wiki/%D0%A1%D0%B2%D1%8F%D0%B7%D1%8B%D0%B2%D0%B0%D0%BD%D0%B8%D0%B5_%D1%81_%D0%B1%D0%B5%D0%BB%D0%BA%D0%B0%D0%BC%D0%B8_%D0%BF%D0%BB%D0%B0%D0%B7%D0%BC%D1%8B" title="Связывание с белками плазмы – Russian" lang="ru" hreflang="ru" data-title="Связывание с белками плазмы" data-language-autonym="Русский" data-language-local-name="Russian" class="interlanguage-link-target"><span>Русский</span></a></li><li class="interlanguage-link interwiki-sl mw-list-item"><a href="https://sl.wikipedia.org/wiki/Vezava_na_plazemske_beljakovine" title="Vezava na plazemske beljakovine – Slovenian" lang="sl" hreflang="sl" data-title="Vezava na plazemske beljakovine" data-language-autonym="Slovenščina" data-language-local-name="Slovenian" class="interlanguage-link-target"><span>Slovenščina</span></a></li><li class="interlanguage-link interwiki-sr mw-list-item"><a href="https://sr.wikipedia.org/wiki/Vezivanje_za_proteine_plazme" title="Vezivanje za proteine plazme – Serbian" lang="sr" hreflang="sr" data-title="Vezivanje za proteine plazme" data-language-autonym="Српски / srpski" data-language-local-name="Serbian" class="interlanguage-link-target"><span>Српски / srpski</span></a></li><li class="interlanguage-link interwiki-sh mw-list-item"><a href="https://sh.wikipedia.org/wiki/Vezivanje_za_proteine_plazme" title="Vezivanje za proteine plazme – Serbo-Croatian" lang="sh" hreflang="sh" data-title="Vezivanje za proteine plazme" data-language-autonym="Srpskohrvatski / српскохрватски" data-language-local-name="Serbo-Croatian" class="interlanguage-link-target"><span>Srpskohrvatski / српскохрватски</span></a></li><li class="interlanguage-link interwiki-fi mw-list-item"><a href="https://fi.wikipedia.org/wiki/Proteiinisitoutuminen_plasmassa" title="Proteiinisitoutuminen plasmassa – Finnish" lang="fi" hreflang="fi" data-title="Proteiinisitoutuminen plasmassa" data-language-autonym="Suomi" data-language-local-name="Finnish" class="interlanguage-link-target"><span>Suomi</span></a></li><li class="interlanguage-link interwiki-tl mw-list-item"><a href="https://tl.wikipedia.org/wiki/Pagbubuklod_ng_plasma_ng_protina" title="Pagbubuklod ng plasma ng protina – Tagalog" lang="tl" hreflang="tl" data-title="Pagbubuklod ng plasma ng protina" data-language-autonym="Tagalog" data-language-local-name="Tagalog" class="interlanguage-link-target"><span>Tagalog</span></a></li><li class="interlanguage-link interwiki-tr mw-list-item"><a href="https://tr.wikipedia.org/wiki/Plazma_proteinine_ba%C4%9Flanma" title="Plazma proteinine bağlanma – Turkish" lang="tr" hreflang="tr" data-title="Plazma proteinine bağlanma" data-language-autonym="Türkçe" data-language-local-name="Turkish" 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.mbox-imageright{border:none;padding:2px 0.5em 2px 0;text-align:center}.mw-parser-output .ambox .mbox-empty-cell{border:none;padding:0;width:1px}.mw-parser-output .ambox .mbox-image-div{width:52px}@media(min-width:720px){.mw-parser-output .ambox{margin:0 10%}}@media print{body.ns-0 .mw-parser-output .ambox{display:none!important}}</style><table class="box-More_citations_needed plainlinks metadata ambox ambox-content ambox-Refimprove" role="presentation"><tbody><tr><td class="mbox-image"><div class="mbox-image-div"><span typeof="mw:File"><a href="/wiki/File:Question_book-new.svg" class="mw-file-description"><img alt="" src="//upload.wikimedia.org/wikipedia/en/thumb/9/99/Question_book-new.svg/50px-Question_book-new.svg.png" decoding="async" width="50" height="39" class="mw-file-element" srcset="//upload.wikimedia.org/wikipedia/en/thumb/9/99/Question_book-new.svg/75px-Question_book-new.svg.png 1.5x, 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Unsourced material may be challenged and removed.<br /><small><span class="plainlinks"><i>Find sources:</i> <a rel="nofollow" class="external text" href="https://www.google.com/search?as_eq=wikipedia&q=%22Plasma+protein+binding%22">"Plasma protein binding"</a> – <a rel="nofollow" class="external text" href="https://www.google.com/search?tbm=nws&q=%22Plasma+protein+binding%22+-wikipedia&tbs=ar:1">news</a> <b>·</b> <a rel="nofollow" class="external text" href="https://www.google.com/search?&q=%22Plasma+protein+binding%22&tbs=bkt:s&tbm=bks">newspapers</a> <b>·</b> <a rel="nofollow" class="external text" href="https://www.google.com/search?tbs=bks:1&q=%22Plasma+protein+binding%22+-wikipedia">books</a> <b>·</b> <a rel="nofollow" class="external text" href="https://scholar.google.com/scholar?q=%22Plasma+protein+binding%22">scholar</a> <b>·</b> <a rel="nofollow" class="external text" href="https://www.jstor.org/action/doBasicSearch?Query=%22Plasma+protein+binding%22&acc=on&wc=on">JSTOR</a></span></small></span> <span class="date-container"><i>(<span class="date">February 2021</span>)</i></span><span class="hide-when-compact"><i> (<small><a href="/wiki/Help:Maintenance_template_removal" title="Help:Maintenance template removal">Learn how and when to remove this message</a></small>)</i></span></div></td></tr></tbody></table> <p><b>Plasma protein binding</b> refers to the degree to which <a href="/wiki/Medication" title="Medication">medications</a> attach to <a href="/wiki/Blood_protein" class="mw-redirect" title="Blood protein">blood proteins</a> within the <a href="/wiki/Blood_plasma" title="Blood plasma">blood plasma</a>. A <a href="/wiki/Drug" title="Drug">drug</a>'s <a href="/wiki/Intrinsic_activity" title="Intrinsic activity">efficacy</a> may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse through <a href="/wiki/Cell_membrane" title="Cell membrane">cell membranes</a>. Common <a href="/wiki/Blood_protein" class="mw-redirect" title="Blood protein">blood proteins</a> that drugs bind to are <a href="/wiki/Human_serum_albumin" title="Human serum albumin">human serum albumin</a>, <a href="/wiki/Lipoprotein" title="Lipoprotein">lipoprotein</a>, <a href="/wiki/Glycoprotein" title="Glycoprotein">glycoprotein</a>, and α, β‚ and γ <a href="/wiki/Globulin" title="Globulin">globulins</a>. </p> <meta property="mw:PageProp/toc" /> <div class="mw-heading mw-heading2"><h2 id="Binding_(drug_distribution)"><span id="Binding_.28drug_distribution.29"></span>Binding (drug distribution)</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=1" title="Edit section: Binding (drug distribution)"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for <a href="/wiki/Plasma_protein" title="Plasma protein">plasma proteins</a>, a proportion of the drug may become bound to the proteins, with the remainder being unbound. If the protein binding is reversible, then a <a href="/wiki/Chemical_equilibrium" title="Chemical equilibrium">chemical equilibrium</a> will exist between the bound and unbound states, such that: </p> <dl><dd>Protein + drug ⇌ Protein-drug complex</dd></dl> <p>Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be <a href="/wiki/Metabolize" class="mw-redirect" title="Metabolize">metabolized</a> and/or excreted. For example, the "fraction bound" of the <a href="/wiki/Anticoagulant" title="Anticoagulant">anticoagulant</a> <a href="/wiki/Warfarin" title="Warfarin">warfarin</a> is 97%. This means that out of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted. </p><p>Protein binding can influence the drug's <a href="/wiki/Biological_half-life" title="Biological half-life">biological half-life</a>. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium. </p><p>Since albumin is alkalotic, acidic and neutral drugs will primarily bind to <a href="/wiki/Human_serum_albumin" title="Human serum albumin">albumin</a>. If albumin becomes saturated, then these drugs will bind to <a href="/wiki/Lipoprotein" title="Lipoprotein">lipoprotein</a>. Basic drugs will bind to the acidic <a href="/wiki/Orosomucoid" title="Orosomucoid">alpha-1 acid glycoprotein</a>. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoproteins. </p> <div class="mw-heading mw-heading2"><h2 id="Impact_of_the_altered_protein_binding">Impact of the altered protein binding</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=2" title="Edit section: Impact of the altered protein binding"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Only the unbound fraction of the drug undergoes metabolism in the liver and other tissues. As the drug dissociates from the protein, more and more drug undergoes metabolism. Changes in the levels of free drug change the volume of distribution because free drug may distribute into the tissues leading to a decrease in plasma concentration profile. For the drugs which rapidly undergo metabolism, <a href="/wiki/Clearance_(medicine)" class="mw-redirect" title="Clearance (medicine)">clearance</a> is dependent on the hepatic blood flow. For drugs which slowly undergo metabolism, changes in the unbound fraction of the drug directly change the clearance of the drug. </p><p>The most commonly used methods for measuring drug concentration levels in the plasma measure bound as well as unbound fractions of the drug. </p><p>The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins. Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein would be saturated with drug and any excess drug would be unbound. If the amount of plasma protein is decreased (such as in <a href="/wiki/Catabolism" title="Catabolism">catabolism</a>, <a href="/wiki/Malnutrition" title="Malnutrition">malnutrition</a>, <a href="/wiki/Liver_disease" title="Liver disease">liver disease</a>, <a href="/wiki/Renal_disease" class="mw-redirect" title="Renal disease">renal disease</a>), there would also be a higher fraction unbound. Additionally, the quality of the plasma protein may affect how many drug-binding sites there are on the protein. </p> <div class="mw-heading mw-heading3"><h3 id="Drug_interactions">Drug interactions</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=3" title="Edit section: Drug interactions"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Using 2 drugs at the same time can sometimes affect each other's fraction unbound. For example, assume that Drug A and Drug B are both protein-bound drugs. If Drug A is given, it will bind to the plasma proteins in the blood. If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of Drug A, since only the unbound fraction may exhibit activity. </p> <table class="wikitable"> <tbody><tr> <th> </th> <th>Before displacement </th> <th>After displacement </th> <th>% increase in unbound fraction </th></tr> <tr> <td><b>Drug A</b> </td> <td> </td> <td> </td> <td> </td></tr> <tr> <td>  <b>% bound</b> </td> <td style="text-align:center;">95 </td> <td style="text-align:center;">90 </td> <td> </td></tr> <tr> <td>  <b>% unbound</b> </td> <td style="text-align:center;">5 </td> <td style="text-align:center;">10 </td> <td style="text-align:center;">+100 </td></tr> <tr> <td><b>Drug B</b> </td> <td> </td> <td> </td> <td> </td></tr> <tr> <td>  <b>% bound</b> </td> <td style="text-align:center;">50 </td> <td style="text-align:center;">45 </td> <td> </td></tr> <tr> <td>  <b>% unbound</b> </td> <td style="text-align:center;">50 </td> <td style="text-align:center;">55 </td> <td style="text-align:center;">+10 </td></tr></tbody></table> <p>Note that for Drug A, the % increase in unbound fraction is 100% – hence, Drug A's pharmacological effect can potentially double (depending on whether the free molecules get to their target before they are eliminated by metabolism or excretion). This change in pharmacologic effect could have adverse consequences. </p><p>However, this effect is really only noticeable in closed systems where the pool of available proteins could potentially be exceeded by the number of drug molecules. Biological systems, such as humans and animals, are open systems where molecules can be gained, lost or redistributed and where the protein pool capacity is almost never exceeded by the number of drug molecules. A drug that is 99% bound means that 99% of the drug molecules are bound to blood proteins not that 99% of the blood proteins are bound with drug. When two, highly protein-bound drugs (A and B) are added into the same biological system it will lead to an initial small increase in the concentration of free drug A (as drug B ejects some of the drug A from its proteins). However, this free drug A is now more available for redistribution into the body tissues and/or for excretion. This means the total amount of drug in the system will decrease quite rapidly, keeping the free drug fraction (the concentration of free drug divided by the total drug concentration) constant and yielding almost no change in clinical effect.<sup id="cite_ref-Toutain2002_1-0" class="reference"><a href="#cite_note-Toutain2002-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> </p><p>The effects of drugs displacing each other and changing the clinical effect (though important in some examples) is vastly overestimated usually and a common example incorrectly used to display the importance of this effect is the anticoagulant <a href="/wiki/Warfarin" title="Warfarin">warfarin</a>. Warfarin is highly protein-bound (>95%) and has a low <a href="/wiki/Therapeutic_index" title="Therapeutic index">therapeutic index</a>. Since a low therapeutic index indicates that there is a high risk of toxicity when using the drug, any potential increases in warfarin concentration could be very dangerous and lead to hemorrhage. In horses, it is very true that if warfarin and <a href="/wiki/Phenylbutazone" title="Phenylbutazone">phenylbutazone</a> are administered concurrently, the horse can develop bleeding issues which can be fatal. This is often explained as being due to the effect of phenylbutazone ejecting warfarin from its plasma protein, thus increasing the concentration of free warfarin and increasing its anticoagulant effect. However, the real problem is that phenylbutazone interferes with the liver's ability to metabolize warfarin so free warfarin cannot be metabolized properly or excreted. This leads to an increase in free warfarin and the resulting bleeding problems.<sup class="noprint Inline-Template Template-Fact" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Citation_needed" title="Wikipedia:Citation needed"><span title="This claim needs references to reliable sources. (March 2020)">citation needed</span></a></i>]</sup> </p> <div class="mw-heading mw-heading2"><h2 id="See_also">See also</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=4" title="Edit section: See also"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><a href="/wiki/Blood_proteins" class="mw-redirect" title="Blood proteins">Blood proteins</a></li> <li><a href="/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetics</a></li></ul> <div class="mw-heading mw-heading2"><h2 id="References">References</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=5" title="Edit section: References"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <style data-mw-deduplicate="TemplateStyles:r1239543626">.mw-parser-output .reflist{margin-bottom:0.5em;list-style-type:decimal}@media screen{.mw-parser-output .reflist{font-size:90%}}.mw-parser-output .reflist .references{font-size:100%;margin-bottom:0;list-style-type:inherit}.mw-parser-output .reflist-columns-2{column-width:30em}.mw-parser-output .reflist-columns-3{column-width:25em}.mw-parser-output .reflist-columns{margin-top:0.3em}.mw-parser-output .reflist-columns ol{margin-top:0}.mw-parser-output .reflist-columns li{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .reflist-upper-alpha{list-style-type:upper-alpha}.mw-parser-output .reflist-upper-roman{list-style-type:upper-roman}.mw-parser-output .reflist-lower-alpha{list-style-type:lower-alpha}.mw-parser-output .reflist-lower-greek{list-style-type:lower-greek}.mw-parser-output .reflist-lower-roman{list-style-type:lower-roman}</style><div class="reflist"> <div class="mw-references-wrap"><ol class="references"> <li id="cite_note-Toutain2002-1"><span class="mw-cite-backlink"><b><a href="#cite_ref-Toutain2002_1-0">^</a></b></span> <span class="reference-text"><style data-mw-deduplicate="TemplateStyles:r1238218222">.mw-parser-output cite.citation{font-style:inherit;word-wrap:break-word}.mw-parser-output .citation q{quotes:"\"""\"""'""'"}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)}.mw-parser-output .id-lock-free.id-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-limited.id-lock-limited a,.mw-parser-output .id-lock-registration.id-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/d/d6/Lock-gray-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-subscription.id-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/a/aa/Lock-red-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-free a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-limited a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-registration a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-subscription a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .cs1-ws-icon a{background-size:contain;padding:0 1em 0 0}.mw-parser-output .cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;color:var(--color-error,#d33)}.mw-parser-output .cs1-visible-error{color:var(--color-error,#d33)}.mw-parser-output .cs1-maint{display:none;color:#085;margin-left:0.3em}.mw-parser-output .cs1-kern-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}@media screen{.mw-parser-output .cs1-format{font-size:95%}html.skin-theme-clientpref-night .mw-parser-output .cs1-maint{color:#18911f}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .cs1-maint{color:#18911f}}</style><cite id="CITEREFToutainBousquet-Melou2002" class="citation journal cs1">Toutain, P. L.; Bousquet-Melou, A. (2002-12-14). <a rel="nofollow" class="external text" href="http://doi.wiley.com/10.1046/j.1365-2885.2002.00442.x">"Free Drug Fraction vs. Free Drug Concentration: A Matter of Frequent Confusion"</a>. <i><a href="/w/index.php?title=Journal_of_Veterinary_Pharmacology_and_Therapeutics&action=edit&redlink=1" class="new" title="Journal of Veterinary Pharmacology and Therapeutics (page does not exist)">Journal of Veterinary Pharmacology and Therapeutics</a></i>. <b>25</b> (6). Wiley inc.: <span class="nowrap">460–</span>463. <a href="/wiki/Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1046%2Fj.1365-2885.2002.00442.x">10.1046/j.1365-2885.2002.00442.x</a>. <a href="/wiki/ISSN_(identifier)" class="mw-redirect" title="ISSN (identifier)">ISSN</a> <a rel="nofollow" class="external text" href="https://search.worldcat.org/issn/0140-7783">0140-7783</a>. <a href="/wiki/PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/12485352">12485352</a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Journal+of+Veterinary+Pharmacology+and+Therapeutics&rft.atitle=Free+Drug+Fraction+vs.+Free+Drug+Concentration%3A+A+Matter+of+Frequent+Confusion&rft.volume=25&rft.issue=6&rft.pages=%3Cspan+class%3D%22nowrap%22%3E460-%3C%2Fspan%3E463&rft.date=2002-12-14&rft.issn=0140-7783&rft_id=info%3Apmid%2F12485352&rft_id=info%3Adoi%2F10.1046%2Fj.1365-2885.2002.00442.x&rft.aulast=Toutain&rft.aufirst=P.+L.&rft.au=Bousquet-Melou%2C+A.&rft_id=http%3A%2F%2Fdoi.wiley.com%2F10.1046%2Fj.1365-2885.2002.00442.x&rfr_id=info%3Asid%2Fen.wikipedia.org%3APlasma+protein+binding" class="Z3988"></span></span> </li> </ol></div></div> <div class="mw-heading mw-heading2"><h2 id="Further_reading">Further reading</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Plasma_protein_binding&action=edit&section=6" title="Edit section: Further reading"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222" /><cite id="CITEREFShargel2005" class="citation book cs1">Shargel, Leon (2005). <i>Applied Biopharmaceutics & Pharmacokinetics</i>. New York: McGraw-Hill, Medical Pub. Division. <a href="/wiki/ISBN_(identifier)" class="mw-redirect" title="ISBN (identifier)">ISBN</a> <a href="/wiki/Special:BookSources/0-07-137550-3" title="Special:BookSources/0-07-137550-3"><bdi>0-07-137550-3</bdi></a>.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Applied+Biopharmaceutics+%26+Pharmacokinetics&rft.place=New+York&rft.pub=McGraw-Hill%2C+Medical+Pub.+Division&rft.date=2005&rft.isbn=0-07-137550-3&rft.aulast=Shargel&rft.aufirst=Leon&rfr_id=info%3Asid%2Fen.wikipedia.org%3APlasma+protein+binding" class="Z3988"></span></li></ul> <p><br /> </p> <div class="navbox-styles"><style data-mw-deduplicate="TemplateStyles:r1129693374">.mw-parser-output .hlist dl,.mw-parser-output .hlist ol,.mw-parser-output .hlist ul{margin:0;padding:0}.mw-parser-output .hlist dd,.mw-parser-output .hlist dt,.mw-parser-output .hlist li{margin:0;display:inline}.mw-parser-output .hlist.inline,.mw-parser-output .hlist.inline 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scope="row" class="navbox-group" style="width:1%;text-align: center;">Excitatory</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Agonist" title="Agonist">Agonist</a></li> <li><a href="/wiki/Endogenous_agonist" title="Endogenous agonist">Endogenous agonist</a></li> <li><a href="/wiki/Irreversible_agonist" title="Irreversible agonist">Irreversible agonist</a></li> <li><a href="/wiki/Partial_agonist" title="Partial agonist">Partial agonist</a></li> <li><a href="/wiki/Superagonist" title="Superagonist">Superagonist</a></li> <li><a href="/wiki/Physiological_agonism_and_antagonism" title="Physiological agonism and antagonism">Physiological agonist</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Inhibitory10" scope="row" class="navbox-group" style="width:1%;text-align: center;">Inhibitory</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Receptor_antagonist" title="Receptor antagonist">Antagonist</a></li> <li><a href="/wiki/Competitive_antagonist" class="mw-redirect" title="Competitive antagonist">Competitive antagonist</a></li> <li><a href="/wiki/Irreversible_antagonist" title="Irreversible antagonist">Irreversible antagonist</a></li> <li><a href="/wiki/Physiological_agonism_and_antagonism" title="Physiological agonism and antagonism">Physiological antagonist</a></li> <li><a href="/wiki/Inverse_agonist" title="Inverse agonist">Inverse agonist</a></li> <li><a href="/wiki/Enzyme_inhibitor" title="Enzyme inhibitor">Enzyme inhibitor</a></li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Drug" title="Drug">Drug</a></li> <li><a href="/wiki/Neurotransmitter" title="Neurotransmitter">Neurotransmitter</a></li> <li><a href="/wiki/Agonist-antagonist" title="Agonist-antagonist">Agonist-antagonist</a></li> <li><a href="/wiki/Pharmacophore" title="Pharmacophore">Pharmacophore</a></li></ul></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Pharmacodynamics" title="Pharmacodynamics">Pharmacodynamics</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Activity_at_receptor20" scope="row" class="navbox-group" style="width:1%;text-align: center;">Activity at receptor</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <li><a href="/wiki/Mechanism_of_action" title="Mechanism of action">Mechanism of action</a></li> <li><a href="/wiki/Mode_of_action" title="Mode of action">Mode of action</a></li> <li><a href="/wiki/Molecular_binding" title="Molecular binding">Binding</a></li> <li><a href="/wiki/Receptor_(biochemistry)" title="Receptor (biochemistry)">Receptor (biochemistry)</a></li> <li><a href="/wiki/Desensitization_(medicine)" title="Desensitization (medicine)">Desensitization (medicine)</a></li> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Other_effects_of_ligand23" scope="row" class="navbox-group" style="width:1%;text-align: center;">Other effects of ligand</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li>Selectivity (<a href="/wiki/Binding_selectivity" title="Binding selectivity">Binding</a>, <a href="/wiki/Functional_selectivity" title="Functional selectivity">Functional</a>)</li> <li><a href="/wiki/Pleiotropy_(drugs)" title="Pleiotropy (drugs)">Pleiotropy (drugs)</a></li> <li><a href="/wiki/Non-specific_effect_of_vaccines" title="Non-specific effect of vaccines">Non-specific effect of vaccines</a></li> <li><a href="/wiki/Adverse_effect" title="Adverse effect">Adverse effect</a></li> <li><a href="/wiki/Toxicity" title="Toxicity">Toxicity</a> (<a href="/wiki/Neurotoxicity" title="Neurotoxicity">Neurotoxicity</a>)</li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Analysis8" scope="row" class="navbox-group" style="width:1%;text-align: center;">Analysis</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Dose%E2%80%93response_relationship" title="Dose–response relationship">Dose–response relationship</a></li> <li><a href="/wiki/Hill_equation_(biochemistry)" title="Hill equation (biochemistry)">Hill equation (biochemistry)</a></li> <li><a href="/wiki/Schild_plot" class="mw-redirect" title="Schild plot">Schild plot</a></li> <li><a href="/wiki/Del_Castillo_Katz_model" class="mw-redirect" title="Del Castillo Katz model">Del Castillo Katz model</a></li> <li><a href="/wiki/Cheng-Prussoff_Equation" class="mw-redirect" title="Cheng-Prussoff Equation">Cheng-Prussoff Equation</a></li> <li>Methods (<a href="/wiki/Organ_bath" title="Organ bath">Organ bath</a>, <a href="/wiki/Ligand_binding_assay" title="Ligand binding assay">Ligand binding assay</a>, <a href="/wiki/Patch_clamp" title="Patch clamp">Patch clamp</a>)</li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Metrics7" scope="row" class="navbox-group" style="width:1%;text-align: center;">Metrics</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Efficacy#Pharmacology" title="Efficacy">Efficacy</a></li> <li><a href="/wiki/Intrinsic_activity" title="Intrinsic activity">Intrinsic activity</a></li> <li><a href="/wiki/Potency_(pharmacology)" title="Potency (pharmacology)">Potency</a> (<a href="/wiki/EC50" title="EC50">EC50</a>, <a href="/wiki/IC50" title="IC50">IC50</a>, <a href="/wiki/Effective_dose_(pharmacology)" title="Effective dose (pharmacology)">ED50</a>, <a href="/wiki/Median_lethal_dose" title="Median lethal dose">LD50</a>, <a href="/wiki/Median_toxic_dose" title="Median toxic dose">TD50</a>)</li> <li><a href="/wiki/Therapeutic_index" title="Therapeutic index">Therapeutic index</a></li> <li><a href="/wiki/Dissociation_constant#Protein-ligand_binding" title="Dissociation constant">Affinity</a></li></ul> </div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetics</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Metrics7" scope="row" class="navbox-group" style="width:1%;text-align: center;">Metrics</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Loading_dose" title="Loading dose">Loading dose</a></li> <li><a href="/wiki/Volume_of_distribution" title="Volume of distribution">Volume of distribution</a> (<a href="/wiki/Initial_volume_of_distribution" title="Initial volume of distribution">Initial</a>)</li> <li><a href="/wiki/Rate_of_infusion" title="Rate of infusion">Rate of infusion</a></li> <li><a href="/wiki/Onset_of_action" title="Onset of action">Onset of action</a></li> <li><a href="/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></li> <li><a class="mw-selflink selflink">Plasma protein binding</a></li> <li><a href="/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="LADME5" scope="row" class="navbox-group" style="width:1%;text-align: center;">LADME</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/ADME" title="ADME">(L)ADME</a>: (<a href="/wiki/Liberation_(pharmacology)" title="Liberation (pharmacology)">Liberation</a>)</li> <li><a href="/wiki/Absorption_(pharmacology)" title="Absorption (pharmacology)">Absorption</a></li> <li><a href="/wiki/Distribution_(pharmacology)" title="Distribution (pharmacology)">Distribution</a></li> <li><a href="/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></li> <li><a href="/wiki/Excretion" title="Excretion">Excretion</a> (<a href="/wiki/Clearance_(pharmacology)" title="Clearance (pharmacology)">Clearance</a>)</li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Compartment_(pharmacokinetics)" title="Compartment (pharmacokinetics)">Compartment</a></li> <li><a href="/wiki/Bioequivalence" title="Bioequivalence">Bioequivalence</a></li></ul></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;">Related<br /> fields</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Neuroscience_and_psychology35" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Neuroscience" title="Neuroscience">Neuroscience</a> and <a href="/wiki/Psychology" title="Psychology">psychology</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <li><a href="/wiki/Neuropsychopharmacology" title="Neuropsychopharmacology">Neuropsychopharmacology</a></li> <li><a href="/wiki/Neuropharmacology" title="Neuropharmacology">Neuropharmacology</a></li> <li><a href="/wiki/Psychopharmacology" title="Psychopharmacology">Psychopharmacology</a></li> <li><a href="/wiki/Electrophysiology" title="Electrophysiology">Electrophysiology</a></li> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Medicine12" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Medicine" title="Medicine">Medicine</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Clinical_pharmacology" title="Clinical pharmacology">Clinical pharmacology</a></li> <li><a href="/wiki/Pharmacy" title="Pharmacy">Pharmacy</a></li> <li><a href="/wiki/Medicinal_chemistry" title="Medicinal chemistry">Medicinal chemistry</a></li> <li><a href="/wiki/Pharmacoepidemiology" title="Pharmacoepidemiology">Pharmacoepidemiology</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Biochemistry_and_genetics33" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Biochemistry" title="Biochemistry">Biochemistry</a> and <a href="/wiki/Genetics" title="Genetics">genetics</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Pharmacoinformatics" title="Pharmacoinformatics">Pharmacoinformatics</a></li> <li><a href="/wiki/Pharmacogenetics" class="mw-redirect" title="Pharmacogenetics">Pharmacogenetics</a></li> <li><a href="/wiki/Pharmacogenomics" title="Pharmacogenomics">Pharmacogenomics</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Toxicology14" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Toxicology" title="Toxicology">Toxicology</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Pharmacotoxicology" title="Pharmacotoxicology">Pharmacotoxicology</a></li> <li><a href="/wiki/Neurotoxicology" class="mw-redirect" title="Neurotoxicology">Neurotoxicology</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Drug_discovery18" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Drug_discovery" title="Drug discovery">Drug discovery</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Classical_pharmacology" title="Classical pharmacology">Classical pharmacology</a></li> <li><a href="/wiki/Reverse_pharmacology" title="Reverse pharmacology">Reverse pharmacology</a></li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Photopharmacology" title="Photopharmacology">Photopharmacology</a></li> <li><a href="/wiki/Immunopharmacology" class="mw-redirect" title="Immunopharmacology">Immunopharmacology</a></li> <li><a href="/wiki/Cell_biology" title="Cell biology">Cell biology</a></li> <li><a href="/wiki/Physiology" title="Physiology">Physiology</a></li></ul></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;">Other</th><td class="navbox-list-with-group navbox-list navbox-even hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"> <li><a href="/wiki/Coinduction_(anesthetics)" title="Coinduction (anesthetics)">Coinduction (anesthetics)</a></li> <li><a href="/wiki/Combination_therapy" title="Combination therapy">Combination therapy</a></li> <li><a href="/wiki/Functional_analog_(chemistry)" title="Functional analog (chemistry)">Functional analog (chemistry)</a></li> <li><a href="/wiki/Polypharmacology" title="Polypharmacology">Polypharmacology</a></li> <li><a href="/wiki/Chemotherapy" title="Chemotherapy">Chemotherapy</a></li> <li><a href="/wiki/Lists_of_drugs" title="Lists of drugs">Lists of drugs</a></li> <li><a href="/wiki/WHO_list_of_essential_medicines" class="mw-redirect" title="WHO list of essential medicines">WHO list of essential medicines</a></li> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Tolerance_and_resistance24" scope="row" class="navbox-group" style="width:1%;text-align: center;">Tolerance and resistance</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Drug_tolerance" title="Drug tolerance">Drug tolerance</a></li> <li><a href="/wiki/Tachyphylaxis" title="Tachyphylaxis">Tachyphylaxis</a></li> <li><a href="/wiki/Drug_resistance" title="Drug resistance">Drug resistance</a></li> <li><a href="/wiki/Antibiotic_resistance" class="mw-redirect" title="Antibiotic resistance">Antibiotic resistance</a></li> <li><a href="/wiki/Multiple_drug_resistance" title="Multiple drug resistance">Multiple drug resistance</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Antimicrobial_pharmacology26" scope="row" class="navbox-group" style="width:1%;text-align: center;">Antimicrobial pharmacology</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Antimicrobial_pharmacodynamics" title="Antimicrobial pharmacodynamics">Antimicrobial pharmacodynamics</a></li> <li><a href="/wiki/Minimum_inhibitory_concentration" title="Minimum inhibitory concentration">Minimum inhibitory concentration</a></li> <li><a href="/wiki/Bacteriostatic_agent" title="Bacteriostatic agent">Bacteriostatic</a></li> <li><a href="/wiki/Minimum_bactericidal_concentration" title="Minimum bactericidal concentration">Minimum bactericidal concentration</a></li> <li><a href="/wiki/Bactericide" title="Bactericide">Bactericide</a></li></ul> </div></td></tr></tbody></table><div> </div></td></tr></tbody></table></div> <!-- NewPP limit report Parsed by mw‐web.codfw.next‐6554649787‐wvxp8 Cached time: 20250305215405 Cache expiry: 2592000 Reduced expiry: false Complications: [vary‐revision‐sha1, show‐toc] CPU time usage: 0.354 seconds Real time usage: 0.444 seconds Preprocessor visited node count: 902/1000000 Post‐expand include size: 64110/2097152 bytes Template argument size: 1259/2097152 bytes Highest expansion depth: 12/100 Expensive parser function count: 3/500 Unstrip recursion depth: 1/20 Unstrip post‐expand size: 17260/5000000 bytes Lua time usage: 0.234/10.000 seconds Lua memory usage: 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