Lipophilicity Influences Drug Binding to α1-Acid Glycoprotein F1/S Variants But Not to the A Variant.

Abstract

ObjectiveHuman α1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these α1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds.MethodsBinding of the marker drugs to human α1-acid glycoprotein was determined by ultra-filtration in the presence or absence of various other drugs. For screening of the α1-acid glycoprotein variants to which the marker drugs became bound, the effects of various other drugs on their binding were studied. The binding data were analyzed using a competitive inhibition model and the relationship between the estimated dissociation constants and physicochemical properties, such as log P, was also analyzed.ResultsThe binding of tamsulosin was significantly decreased by aprindine, carvedilol, erythromycin, thioridazine, and warfarin, but not by disopyramide. The dissociation constants of drugs bound to F1/S variants were significantly correlated with their lipophilicity, but those for the A variant were not.ConclusionsWe were able to develop a simple screening method for determining individual α1-acid glycoprotein variants to which drugs would bind. The binding of drugs to F1/S variants may be determined mainly by drug lipophilicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-017-0193-9) contains supplementary material, which is available to authorized users.