Plasma protein binding

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

A drug's efficacy may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, ß‚ and γ globulins.

A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for plasma protein, a proportion of the drug may become bound to plasma proteins, with the remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states, such that:

Protein + drug ⇌ Protein-drug complex

Notably, it is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted. For example, the "fraction bound" of the anticoagulant warfarin is 97%. This means that 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.

Protein binding can influence the drug's biological half-life in the body. 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.

Since albumin is basic, acidic and neutral drugs will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein. Basic drugs will bind to the acidic alpha-1 acid glycoprotein. This is significant because various medical conditions may affect the levels of albumin, alpha-1 acid glycoprotein, and lipoprotein.

Variables affecting protein binding

Since it is the fraction unbound that exhibits pharmacologic effects, it is important to know what may affect the fraction unbound.

The fraction unbound can be altered by a number of variables, such as the concentration of drug in the body, the amount & 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 catabolism, malnutrition, liver disease, renal disease), 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.

Drug interactions

Using 2 drugs at the same time may 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. See the example below:

Before Displacement After Displacement % increase in unbound fraction
Drug A
  % bound 95 90
  % unbound 5 10 +100
Drug B
  % bound 50 45
  % unbound 50 55 +10

Note that for Drug A, the % increase in unbound fraction is 100%-- hence, Drug A's pharmacologic effect has doubled. This change in pharmacologic effect could have adverse consequences.

This effect of protein binding is most significant with drugs that are highly protein-bound (>95%) and have a low therapeutic index, such as warfarin. A low therapeutic index indicates that there is a high risk of toxicity when using the drug. Since warfarin is an anticoagulant with a low therapeutic index, warfarin may cause bleeding if the correct degree of pharmacologic effect is not maintained. If a patient on warfarin takes another drug that displaces warfarin from plasma protein, it could result in an increased risk of bleeding.

Plasma protein binding prediction software

Quantum Plasma Protein Binding

References

  1. Shargel, Leon (2005). Applied Biopharmaceutics & Pharmacokinetics. New York: McGraw-Hill, Medical Pub. Division. ISBN 0071375503. 

See also


Cost Effectiveness of Plasma protein binding

| group5 = Clinical Trials Involving Plasma protein binding | list5 = Ongoing Trials on Plasma protein binding at Clinical Trials.govTrial results on Plasma protein bindingClinical Trials on Plasma protein binding at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Plasma protein binding | list6 = US National Guidelines Clearinghouse on Plasma protein bindingNICE Guidance on Plasma protein bindingNHS PRODIGY GuidanceFDA on Plasma protein bindingCDC on Plasma protein binding


| group7 = Textbook Information on Plasma protein binding | list7 = Books and Textbook Information on Plasma protein binding


| group8 = Pharmacology Resources on Plasma protein binding | list8 = AND (Dose)}} Dosing of Plasma protein bindingAND (drug interactions)}} Drug interactions with Plasma protein bindingAND (side effects)}} Side effects of Plasma protein bindingAND (Allergy)}} Allergic reactions to Plasma protein bindingAND (overdose)}} Overdose information on Plasma protein bindingAND (carcinogenicity)}} Carcinogenicity information on Plasma protein bindingAND (pregnancy)}} Plasma protein binding in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Plasma protein binding


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Plasma protein binding | list9 = AND (pharmacogenomics)}} Genetics of Plasma protein bindingAND (pharmacogenomics)}} Pharmacogenomics of Plasma protein bindingAND (proteomics)}} Proteomics of Plasma protein binding


| group10 = Newstories on Plasma protein binding | list10 = Plasma protein binding in the newsBe alerted to news on Plasma protein bindingNews trends on Plasma protein binding


| group11 = Commentary on Plasma protein binding | list11 = Blogs on Plasma protein binding

| group12 = Patient Resources on Plasma protein binding | list12 = Patient resources on Plasma protein bindingDiscussion groups on Plasma protein bindingPatient Handouts on Plasma protein bindingDirections to Hospitals Treating Plasma protein bindingRisk calculators and risk factors for Plasma protein binding


| group13 = Healthcare Provider Resources on Plasma protein binding | list13 = Symptoms of Plasma protein bindingCauses & Risk Factors for Plasma protein bindingDiagnostic studies for Plasma protein bindingTreatment of Plasma protein binding

| group14 = Continuing Medical Education (CME) Programs on Plasma protein binding | list14 = CME Programs on Plasma protein binding

| group15 = International Resources on Plasma protein binding | list15 = Plasma protein binding en EspanolPlasma protein binding en Francais

| group16 = Business Resources on Plasma protein binding | list16 = Plasma protein binding in the MarketplacePatents on Plasma protein binding

| group17 = Informatics Resources on Plasma protein binding | list17 = List of terms related to Plasma protein binding


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