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

在白人中进行的大型临床试验显示β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有益作用。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，高加索人和日本人之间卡维地洛推荐剂量的差异以及药物治疗结果的个体间差异的机制仍不清楚。细胞色素P450（CYP）2D 6参与β-受体阻滞剂的肝脏代谢，但CYP 2D 6的等位基因频率存在明显的种族间差异。我们以前报道过，在日本CYP 2D 6患者中，美托洛尔的口服清除率（CL/F）值显著降低^*10。本研究的目的是阐明卡维地洛和比索洛尔药代动力学变异性的机制，并评价β受体阻滞剂在疾病状态下的药效学变异性。 ...更多信息 在日本健康志愿者中，评价了卡维地洛（2D 6，2C 9，2C 19，3A 5）和UDP-葡萄糖醛酸转移酶（UGT）2B 7的遗传多态性以及多药耐药1（MDR 1）对卡维地洛药代动力学的影响。在携带CYP 2D 6 ^*10等位基因的患者中，R-和S-卡维地洛的CL/F值显著降低，表明CYP 2D 6 ^*10是导致药物药代动力学变异性较大的主要因素之一。相比之下，日本患者中比索洛尔的药代动力学变异性较小，前提是在预测药物CL/F时考虑体重和肾功能。此外，我们阐明了比索洛尔在实验性肾衰竭大鼠中的药代动力学，然后评价了肾衰竭对比索洛尔药效学的影响;然而，药物的β-阻断作用不受肾衰竭的影响。我们的研究结果可能为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