Differences in plasma binding of drugs between Caucasians and Chinese subjects

Abstract

Interracial differences in drug responsiveness can be accounted for, at least in part, by differences in drug disposition. To investigate whether reversible interactions with plasma constituents may be a contributing factor in such differences, the binding of a number of model drugs was studied in plasma obtained from healthy Caucasian and Chinese subjects (n = 8 in each group). The unbound fractions of drugs binding to sites I and II on albumin (warfarin, diazepam, and salicylic acid) were similar in the two groups, and there was no difference in the plasma albumin concentration. By contrast, the percentages of unbound diphenhydramine (26.40% +/- 6.46% versus 18.30% +/- 4.31, mean +/- SD) and propranolol (13.81% +/- 1.33% versus 11.68% +/- 2.37) were significantly (p less than 0.05) higher in Chinese subjects compared to Caucasians. A 30% difference was also observed in the nonlinear binding of disopyramide. These basic drugs interact with both alpha 1-acid glycoprotein and albumin, and the lower binding was associated with a lower plasma concentration of the acute-phase reactant in Chinese subjects. Kinetic analysis of the disopyramide binding isotherm was also suggestive of reduced binding capacity with no change in binding affinity. The reason for the racial difference in the alpha 1-acid glycoprotein level is unknown; however, for drugs extensively bound to this glycoprotein the resulting difference in unbound fraction would be expected to have predictable pharmacokinetic consequences that may result in differences in responsiveness. Determination of plasma binding, especially of drugs interacting with alpha 1-acid glycoprotein, should therefore be an essential component of comparative studies in subjects of different races.