{"id":750,"date":"2020-02-17T21:43:04","date_gmt":"2020-02-17T16:13:04","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=750"},"modified":"2020-02-17T21:43:04","modified_gmt":"2020-02-17T16:13:04","slug":"plasma-protein-binding","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/plasma-protein-binding\/","title":{"rendered":"Plasma protein binding"},"content":{"rendered":"\n<p><strong>Plasma protein binding<\/strong><\/p>\n\n\n\n<ul><li>Drug protein binding is the reversible interaction of drugs with proteins in plasma.<\/li><li>Free drug + free protein \u00e0 drug-protein complex<strong><\/strong><\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"264\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-307.png?w=480\" alt=\"\" class=\"wp-image-787\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-307.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-307-300x165.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ul><li>Drug protein binding may be:<ul><li><strong>Reversible<\/strong>: Hydrogen bonds or vander Walls forces<\/li><\/ul><ul><li><strong>Irreversible<\/strong>: covalent bond<\/li><\/ul><ul><li>E.g.- Alkylating agents rarely&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;<ul><li>Hepatotoxicity of acetaminophen (high doses)<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Binding of drug<\/strong><\/p>\n\n\n\n<ul><li>1) <strong>Blood components:<\/strong>&nbsp; a) plasma proteins b) blood cells<\/li><li>2) <strong>Extra vascular tissues:<\/strong>&nbsp; a) proteins b) bones c) fats<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"468\" height=\"314\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-308.png?w=468\" alt=\"\" class=\"wp-image-788\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-308.png 468w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-308-300x201.png 300w\" sizes=\"(max-width: 468px) 100vw, 468px\" \/><\/figure>\n\n\n\n<p><strong>Albumin<\/strong><\/p>\n\n\n\n<ul><li>Each albumin molecule has at least 6 distinct binding sites for drugs and endogenous compounds.<\/li><li>Two of these very tightly and specifically bind long chain fatty acids.<\/li><li>There is another site which selectively binds bilirubin.<\/li><li>There are two major drug binding sites called <strong>site I <\/strong>and <strong>site II <\/strong>which mainly bind acidic drugs.<\/li><li>&nbsp;<strong>Site I <\/strong>binds drugs such as warfarin and phenylbutazone, whereas <strong>site II <\/strong>binds drugs such as diazepam and ibuprofen.<\/li><li>Drugs may be categorized into two groups with respect to albumin binding:<\/li><li><strong>Class I<\/strong>: Drugs that have a low dose\/albumin binding ratio.&nbsp; Albumin binding sites exceed the availability of the drug. The bound fraction consists of a significant proportion of the total drug.&nbsp; Many clinically useful drugs are Class I types.<\/li><li><strong>Class II:&nbsp; <\/strong>Drugs that have a high dose\/albumin capacity ratio.&nbsp; The majority of the drug exists in the free state, bound drug is a small proportion of the total drug.&nbsp; Class II drugs can displace Class I drugs from albumin dramatically increasing the amount of free (active) drug.<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"327\" height=\"574\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-309.png?w=327\" alt=\"\" class=\"wp-image-789\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-309.png 327w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-309-171x300.png 171w\" sizes=\"(max-width: 327px) 100vw, 327px\" \/><\/figure>\n\n\n\n<p>TYPES OF DRUG-PROTEIN BINDING<\/p>\n\n\n\n<ul><li><strong>Reversible<\/strong><\/li><li><strong>Irreversible<\/strong>&nbsp; eg.Chemical carcinogenesis &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Acetaminophen hepatotoxicity<\/li><\/ul>\n\n\n\n<p><strong>Drug Displacement<\/strong><\/p>\n\n\n\n<ul><li><strong>Competitive<\/strong> \u2013drug bind to same site<\/li><li><strong>Non-competitive<\/strong>-inhibitory drug causing conformational change in protein molecule that inhibit binding of first drug<\/li><li>Drug acting as a displacing agent has to be present in1)high conc. 2)high affinity to protein<\/li><li>Acidic drugs do not displace basic drugs &amp; <em>vice versa.<\/em><\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"306\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-310.png?w=480\" alt=\"\" class=\"wp-image-790\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-310.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-310-300x191.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<p><strong>Binding of Drugs to RBC<\/strong><\/p>\n\n\n\n<ul><li>Lipophilic molecules dissolved in the lipid material of the RBC membrane<\/li><li>Anions can be attracted to and enter the positively charged pores of RBC<\/li><li>Lipophilic drugs may be absorbed to RBC membrane due to change of:<ul><li>Change of shape of membrane and membrane proteins<\/li><\/ul><ul><li>Membrane extension which may lead to change of RBC shape<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>The RBC binding sites are:<\/strong><\/p>\n\n\n\n<ul><li>Intracellular proteins<ul><li>Hemoglobin<\/li><\/ul><ul><li>Carbonic anhydrase<\/li><\/ul><ul><li>Cell membrane<\/li><\/ul><ul><li>ATPase<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Binding of drug to blood cells<\/strong><\/p>\n\n\n\n<ul><li><strong>hemoglobin &#8211; <\/strong>bind to phenytoin, pentobarbital , phenothiazine<\/li><li><strong>carbonic anhydrase- <\/strong>drug bind&nbsp; like acetazolamide , chlorthalidone<\/li><li><strong>cell membrane <\/strong>\u2013 imipramine , chlorpramazine bind to RBCs cell membrane<\/li><\/ul>\n\n\n\n<p><strong>The Pharmacokinetic Importance of Protein Binding<\/strong><\/p>\n\n\n\n<ul><li>Drug-protein binding influences <strong>the distribution &amp; equilibrium<\/strong> of the drug.<\/li><li>Plasma proteins exert a <strong>buffer and transport function<\/strong> in the distribution process.<\/li><li>Only <strong>free drug can leave the circulatory system and diffuse<\/strong> into the tissue.<\/li><li>When free drug is eliminated by the body, some bound drug is released from protein binding.&nbsp;<\/li><li>Some drugs persist in the body for three days by this mechanism.<\/li><li><strong>2 drugs <\/strong>given concurrently &amp; highly bound to the same site on a plasma protein <strong>will compete for the binding site resulting in a greater proportion of free drug<\/strong>.<\/li><li>This effect may increase the freedrug to<strong>toxic levels.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Binding &amp; interaction of drugs to protein<\/strong><\/p>\n\n\n\n<p>&nbsp;&nbsp; <strong>Binding of drugs may :<\/strong><\/p>\n\n\n\n<ul><li><strong>Facilitate the distribution<\/strong> of drugs<\/li><li><strong>Inactivate the drug<\/strong> by not enabling a sufficient concentration of free drug to develop at a receptor site<\/li><li><strong>Retard the excretion<\/strong> of a drug<\/li><\/ul>\n\n\n\n<p><strong>&nbsp;&nbsp;&nbsp; Interaction of drugs may cause:<\/strong><\/p>\n\n\n\n<ul><li>Displacement of body hormones or co-administered agent<\/li><li>Change the configuration of protein to another structure capable of binding a co-administered agent<\/li><li><strong>Inactivates the drug<\/strong> biologically by forming a drug-protein complex<\/li><\/ul>\n\n\n\n<ul><li>Many drugs bind to the same receptor site but drugs with higher affinity will replace those drugs with lower affinity by competition<\/li><li><strong>Only free and unbound drugs exert therapeutic effect by interacting with receptors<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Factor affecting drug protein binding<\/strong><\/p>\n\n\n\n<p><strong>1. Factors relating to the drug<\/strong><strong><\/strong><\/p>\n\n\n\n<ol type=\"a\"><li>Physicochemical characteristic of drug<\/li><li>Concentration of drug in the body<\/li><li>Affinity of drug for a particular protein.<\/li><\/ol>\n\n\n\n<p><strong>2. Factor relating to the protein<\/strong><strong><\/strong><\/p>\n\n\n\n<ol type=\"a\"><li>Physicochemical characteristic of the protein<\/li><li>Concentration of protein<\/li><li>No. of binding site on protein<\/li><\/ol>\n\n\n\n<p><strong>3. Drug interaction<\/strong><\/p>\n\n\n\n<p><strong>4. Patient related factor<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"513\" height=\"300\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-311.png?w=513\" alt=\"\" class=\"wp-image-791\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-311.png 513w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-311-300x175.png 300w\" sizes=\"(max-width: 513px) 100vw, 513px\" \/><\/figure>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"360\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-312.png?w=480\" alt=\"\" class=\"wp-image-792\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-312.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-312-300x225.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"360\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-313.png?w=480\" alt=\"\" class=\"wp-image-793\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-313.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-313-300x225.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<p><strong>Displacement of drugs from Protein Binding is due to:<\/strong><\/p>\n\n\n\n<ul><li>Total amount of protein-bound drug in that body<\/li><li>Extent of tissue binding structure<\/li><li>&nbsp;Apparent volume of distribution<\/li><\/ul>\n\n\n\n<p><strong><u>Methods for studying Drug-Protein binding<\/u><\/strong><\/p>\n\n\n\n<ul><li>Equilibrium dialysis<\/li><li>Dynamic dialysis<\/li><li>Diafiltration<\/li><li>Ultrafiltration<\/li><li>Ultracentrifugation<\/li><li>Gel chromatography<\/li><li>Spectrophotometry<\/li><li>Electrophoresis<\/li><li>Optical rotatory dispersion and circulatory dichroism<\/li><\/ul>\n\n\n\n<p>the most suitable <strong>in-vitro <\/strong>experimental methods are equilibrium dialysis, ultracentrifugation, and ultrafiltration.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The concentration of drug in saliva,tears or the erythrocyte\/plasma drug concentration ratio may give a useful measure of <strong>in-vivo<\/strong> binding of selected drugs-for example, phenytoin. Unfortunately, none of these methods is suitable for large-scale routine use at present.<\/p>\n\n\n\n<p><strong>Regulatory Guidelines<\/strong><\/p>\n\n\n\n<ul><li>Before initiating human trials: \u201cIn vitro\u201d PPB data for animals and humans should be evaluated<\/li><\/ul>\n\n\n\n<ul><li>If extensively protein bound, the risk of displacement of other drugs should be investigated<\/li><\/ul>\n\n\n\n<p><strong>Examples related to protein binding of drugs<\/strong><\/p>\n\n\n\n<ul><li>Aspirin acetylates the lysine residue of albumin, which changes the binding capacity of this protein for anti-inflammatory drugs.<\/li><li>In infants, displacement of bilirubin by sulfonamides cause kernictirus<\/li><li>Digoxin binds to cardiac tissues of heart. Quinine causes rise in steady state plasma level of digoxin due to displacement of tissue bound digoxin<\/li><li>Warfarin, when co-administered with phenylbutazone, causes bleeding due to displacement reaction.<\/li><li>Diazepam is considered restrictively eliminated while propranolol non-restrictively eliminated.\u00a0<\/li><li>Plasma protein binding acts as a carrier mechanism to hasten drug elimination e.g. excretion of penicillin, metabolism of lignocaine.<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Plasma protein binding Drug protein binding is the reversible interaction of drugs with proteins in plasma. Free drug + free protein \u00e0 drug-protein complex Drug protein binding may be: Reversible: Hydrogen bonds or vander Walls forces Irreversible: covalent bond E.g.- Alkylating agents rarely&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Hepatotoxicity of acetaminophen (high doses) Binding of drug 1) Blood components:&nbsp; a)[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/750"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=750"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/750\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=750"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=750"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=750"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}