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Encyclopedia > Plasma protein binding

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, β‚ and γ globulins. Blood plasma is the liquid component of blood, in which the blood cells are suspended. ... It has been suggested that this article or section be merged into serum albumin. ... A lipoprotein is a biochemical assembly that contains both proteins and lipids. ... N-linked protein glycosylation (N-glycosylation of N-glycans) at Asn residues (Asn-x-Ser/Thr motifs) in glycoproteins[1]. Glycoproteins are proteins that contain oligosaccharide chains (glycans) covalently attached to their polypeptide backbones. ... Globulin is one of the two types of serum proteins, the other being albumin. ...


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: A burette, an apparatus for carrying out acid-base titration, is an important part of equilibrium chemistry. ...

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. An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ... Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is an anticoagulant medication that is administered orally or, very rarely, by injection. ...


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. The biological half-life of a substance is the time required for half of that substance to be removed from an organism by either a physical or a chemical process. ...


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.

Contents

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. Anabolism is the aspect of metabolism that contributes to growth. ... Percentage of population affected by malnutrition by country, according to United Nations statistics. ... The liver is an organ in vertebrates including humans. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ...


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. The therapeutic index of a medication is a comparison of the amount that causes the therapeutic effect to the amount that causes toxic effects. ...


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. 

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