A Molecular Functional Study on the Interactions of Drugs with Plasma Proteins

The binding of drugs to plasma proteins, such as albumin and α1-acid glycoprotein (AGP) is a major determinant in the disposition of drugs. A topology analysis of drug binding sites on HSA and AGP was determined using various methods, including spectroscopy, QSAR, photoaffinity labeling and site directed mutagenesis. Recombinant albumin was found to be useful for rapidly identifying drug binding sites. The binding sites on AGP are not completely separated but are partially overlapped, and Trp, Tyr, Lys and His residues in the drug binding pockets play important roles in this process. Drug displacement is somewhat complex, due to the involvement of multiple effects. The reduced binding in uremic patients may be explained by a mechanism that involves a combination of direct displacement by free fatty acids as well as cascade effects of free fatty acids and unbound uremic toxins for significant inhibition in serum binding. Albumin-containing dialysate is useful for the extracorporeal removal of endogenous toxins and in the treatment of drug overdoses. Oxidized albumin is a useful biomarker for the quantitative and qualitative evaluation of oxidative stress. Interestingly, AGP undergoes a structural transition to a unique structure that differs from the native and denatured states, when it interacts with membranes.