Mechanism of the pharmacokinetic variability and race difference of β-blockers

白种人的大型临床试验显示p受体阻滞剂（卡维地洛、美托洛尔和比索洛尔）对慢性心力衰竭患者有益。另一方面，低剂量卡维地洛在日本被批准用于治疗慢性心力衰竭。然而，高加索人和日本人在卡维地洛推荐剂量上的差异机制以及该药治疗结果的巨大个体差异仍不清楚。细胞色素P450 (CYP) 2D6参与β-阻滞剂的肝脏代谢，但在CYP2D6的等位基因频率上存在明显的种族差异。我们之前报道过日本CYP2D6^*10患者美托洛尔的口服清除率（CL/F）值显著降低。本研究旨在阐明卡维地洛和比索洛尔的药代动力学变异性机制，并评价β受体阻滞剂在疾病状态下的药效学变异性。研究了CYP （2D6、2C9、2C19、3A5）和udp -葡萄糖醛基转移酶（UGT） 2B7遗传多态性以及多药耐药1 （MDR1）对卡维地洛在日本健康志愿者体内药代动力学的影响。CYP2D6^*10等位基因患者R-和s -卡维地洛的CL/F值显著降低，提示CYP2D6^*10是造成该药代动力学变异性较大的主要因素之一。相比之下，如果考虑体重和肾功能来预测药物的CL/F，比索洛尔在日本患者中的药代动力学变异性较小。此外，我们阐明了比索洛尔在实验性肾功能衰竭大鼠体内的药代动力学，并评价肾功能衰竭对比索洛尔药效学的影响；然而，药物的β阻断作用不因肾功能衰竭而改变。我们的结果可能为β受体阻滞剂在心力衰竭治疗中的应用提供有用的信息。少

Large clinical trials in Caucasians have shown a beneficial effect of p-blockers (carvedilol, metoprolol, and bisoprolol) on patients with chronic heart failure. On the other hand, low-dose carvedilol was approved for management of chronic heart failure in Japan. However, the mechanisms of difference between Caucasian and Japanese in the recommended dose of carvedilol and of large interindividual variability in the therapeutic outcomes of the drug were still unclear. The cytochrome P450 (CYP) 2D6 is involved in the hepatic metabolism of β-blockers, but a pronounced interethnic difference is present in the allele frequencies of CYP2D6. We previously reported that the oral clearance (CL/F) value of metoprolol was significantly decreased in Japanese patients with CYP2D6^*10. The purpose of this study was to clarify the mechanisms involved in the pharmacokinetic variability of carvedilol and bisoprolol, and to evaluate the pharmacodynamic variability of β-blockers under disease condition.W … More e evaluated the effect of genetic polymorphisms of CYP (2D6, 2C9, 2C19, 3A5) and UDP-glucuronosyl-transferase (UGT) 2B7, and multidrug resistance 1 (MDR1) on the pharmacokinetics of carvedilol in healthy Japanese volunteers. The CL/F value of R- and S-carvedilol was significantly decreased in patients with CYP2D6^*10 allele, suggesting that CYP2D6^*10 is one of the major factors responsible for large pharmacokinetic variability of the drug. In contrast, the pharmacokinetic variability of bisoprolol was small in Japanese patients, provided that both body weight and renal function are taken into account for the prediction of CL/F of the drug. In addition, we elucidated the pharmacokinetics of bisoprolol in rats with experimental renal failure, and then evaluated the effect of renal failure on the pharmacodynamics of bisoprolol ; however, β-blocking action of the drug was not altered by renal failure. Our results may provide useful information about the use of β-blockers in management of heart failure. Less