Zhou H H, Koshakji R P, Silberstein D J, Wilkinson G R, Wood A J
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232.
N Engl J Med. 1989 Mar 2;320(9):565-70. doi: 10.1056/NEJM198903023200905.
To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.
为了确定β受体阻滞剂的药代动力学和药效学在不同种族群体中是否存在差异，我们让10名华裔男性和10名美国白人男性每8小时服用10、20、40和80毫克普萘洛尔；给药剂量随机安排，每个剂量服用一天。通过测量仰卧位、直立位以及跑步机运动试验期间心率和血压的降低程度来评估β受体阻滞程度。华裔受试者对普萘洛尔的β受体阻滞作用的敏感性至少是白人受试者的两倍，这体现在仰卧位（使心率降低20%时的平均（±标准误）血浆浓度为197±31 vs. 536±58纳摩尔/升；P<0.05）、直立位（131±27 vs. 343±39纳摩尔/升；P<0.05）以及运动试验后（96±12 vs. 185±23纳摩尔/升；P<0.05）。此外，华裔受试者对普萘洛尔的降压作用更为敏感，这体现在仰卧位使血压降低10%时的浓度（73±5 vs. 748±7纳摩尔/升；P<0.01）和直立位（89±5 vs. 401±6纳摩尔/升；P<0.01）。两组之间淋巴细胞的β受体密度或亲和力未发现差异。华裔组血浆中普萘洛尔的游离分数高45%，这可能促成了药物作用增强，但不能完全解释这一现象。该组代谢普萘洛尔比白人组更快，由于通过多种代谢途径代谢增加，导致口服剂量的清除率高76%（3740±737 vs. 2125±214毫升/分钟；P<0.05）。我们得出结论，华裔男性比白人男性对普萘洛尔对心率和血压的影响更为敏感。蛋白结合减少可能部分起作用，但大部分影响仍有待解释。
