Zhou H H, Adedoyin A, Wilkinson G R
Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232.
Clin Pharmacol Ther. 1990 Jul;48(1):10-7. doi: 10.1038/clpt.1990.111.
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.
药物反应性的种族差异至少部分可归因于药物处置的差异。为了研究与血浆成分的可逆相互作用是否可能是造成这种差异的一个因素，我们对从健康的白种人和中国受试者（每组n = 8）获得的血浆中多种模型药物的结合情况进行了研究。两组中与白蛋白上I位点和II位点结合的药物（华法林、地西泮和水杨酸）的游离分数相似，血浆白蛋白浓度也没有差异。相比之下，中国受试者中苯海拉明（26.40% +/- 6.46% 对18.30% +/- 4.31，均值 +/- 标准差）和普萘洛尔（13.81% +/- 1.33% 对11.68% +/- 2.37）的游离百分比显著高于白种人（p < 0.05）。在丙吡胺的非线性结合方面也观察到了30%的差异。这些碱性药物与α1 - 酸性糖蛋白和白蛋白都有相互作用，较低的结合与中国受试者中急性期反应物的较低血浆浓度相关。丙吡胺结合等温线的动力学分析也表明结合能力降低而结合亲和力没有变化。α1 - 酸性糖蛋白水平种族差异的原因尚不清楚；然而，对于与这种糖蛋白广泛结合的药物，由此产生的游离分数差异预计会产生可预测的药代动力学后果，可能导致反应性的差异。因此，测定血浆结合情况，尤其是与α1 - 酸性糖蛋白相互作用的药物的血浆结合情况，应该是不同种族受试者比较研究的一个重要组成部分。
