EVIDENCE FOR DIFFERENCES IN THE BINDING OF DRUGS TO THE 2 MAIN GENETIC-VARIANTS OF HUMAN ALPHA(1)-ACID GLYCOPROTEIN

1 Human alpha1-acid glycoprotein (AAG), a plasma transport protein. ha s three main genetic variants, F1, S and A. Native commercial AAG (a m ixture of almost equal proportions of these three variants) has been s eparated by chromatography into variants which correspond to the prote ins of the two genes which code for AAG in humans: the A variant and a mixture of the F1 and S variants (60% F1 and 40% S). Their binding pr operties towards imipramine, warfarin and mifepristone were studied by equilibrium dialysis. 2 The F1S variant mixture strongly bound warfar in and mifepristone with an affinity of 1.89 and 2.06 x 10(6) l mol-1 respectively but had a low affinity for imipramine. Conversely, the A variant strongly bound imipramine with an affinity of 0.98 x 10(6) l m ol-1. The low degree of binding of warfarin and mifepristone to the A variant sample was explained by the presence of protein contaminants i n this sample. These results indicate specific drug transport roles fo r each variant, with respect to its separate genetic origin. 3 Control binding experiments performed with (unfractionated) commercial AAG an d with AAG isolated from individuals with either the F1/A or S/A pheno types, agreed with these findings. The results for the binding of warf arin and mifepristone by the AAG samples were similar to those obtaine d with the F1S mixture: the mean high--affinity association constant o f the AAG samples for each drug was of the same order as that of the F 1S mixture; the decrease in the number of binding sites of the AAG sam ples, as compared with the F1S mixture, was explained by the smaller p roportion of variants F1 and/or S in these samples. Conversely, result s of the imipramine binding study with the AAG samples concurred with those for the binding of this basic drug by the A variant, with respec t to the proportion of the A variant in these samples.