Differential binding of disopyramide and warfarin enantiomers to human α1‐acid glycoprotein variants

Aims The F1S and A genetic variants of α1‐acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding abilities. We have studied the stereoselective binding ability of each of the AAG variants using enantiomers of disopyramide (DP) and warfarin (WR). Methods The AAG variants were separated by hydroxyapatite chromatography. Binding of drug enantiomers to the AAG variants was studied by the Hummel–Dreyer method. The characteristics of the binding activities were examined by Scatchard plot analysis. The first five amino‐terminal amino acids (residues 112–116) of the cyanogen bromide (CNBr) fragment (residues 112–181) of each of the separated AAG fractions were elucidated by Edman degradation. Results Commercial AAG was separated into two main fractions. Residues 112–116 of fraction 2 were identical to the amino acid sequences predicted from the AAG A gene, LAFDV, and encode the F1S variant. In fraction 3, the deduced amino acid sequence of the AAG B gene, FGSYL, was established, and encodes the A variant. The binding affinities of both DP enantiomers in fraction 3 were significantly higher than those in fraction 2. The differences between dissociation constants (Kd) in fractions 2 and 3 were 5.2‐fold for (S)‐DP (P