Protein binding

A drug’s efficacy may be affected by the extent of binding to proteins within blood, plasma, tissues including brain tissue. Common proteins in blood that drugs bind to are serum albumin, lipoprotein, glycoprotein, α, β‚ and γ globulins. Drugs that traverse the BBB may bind brain tissues. The higher the drug free fraction (fu), the more efficiently it can permeate cell membranes or diffuse. 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

Only the unbound fraction is free to exhibit pharmacologic effects and to undergo metabolism or excretion. Equilibrium dialysis is an accurate and reliable method for determining protein binding affinities (whole blood, plasma or tissues) to chemical substances of low molecular weight. Determining protein binding is a critical phase of drug development as it influences compound dosing, efficacy, clearance rate and potential for drug interactions. 

Also, in vitro drug binding to microsomes during metabolic stability incubations may lead to underestimations in clearance rates, leading to poor IVIV correlations. If fu inc (free fraction in the incubation) is known it can be accounted for and in vitro clearance rates corrected.

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