Luo X, Lei Y, He L, Liu W, Li M, Ran L, Yu M, Guo X, Yu P, Liu Z, Cheng Z
School of Life Sciences, Central South University, Changsha, China.
Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha, China.
J Clin Pharm Ther. 2015 Oct;40(5):561-565. doi: 10.1111/jcpt.12310. Epub 2015 Jul 27.
Nebivolol, a clinically important antihypertensive drug, mainly metabolized by cytochrome P450 (CYP) 2D6, shows wide interindividual variability in pharmacokinetics. The CYP2D610 allele (100C>T; rs1065852), present at a high frequency in the Chinese population, is associated with alteration in the pharmacokinetics of many drugs, but its effect on the pharmacokinetics of nebivolol is unknown. The aim of our study was to investigate whether the CYP2D610 genotype and phenotype are associated with changes in the pharmacokinetics of nebivolol in Chinese subjects.
Twenty-four healthy subjects were divided into three groups according to CYP2D6*1/1 (n = 7), CYP2D61/10 (n = 5) and CYP2D610/*10 (n = 12) genotypes. The *1/*1 homozygotes and *1/*10 heterozygotes were C allele carriers. All subjects received oral single dose of nebivolol and dextromethorphan. Blood and urine samples were gathered at various times.
There were no statistically significant differences in the pharmacokinetics of nebivolol between the three CYP2D610 genotypes, and no gene-dose effect was seen. The pharmacokinetic parameters of CYP2D610/10 subjects were also similar to those of CYP2D61 carriers. A weak relationship between CYP2D6 phenotype and nebivolol clearance was found.
The CYP2D610 genotype and phenotype were not associated with significant alterations in the pharmacokinetics of nebivolol. CYP2D610 alone does not account for the large interindividual differences observed in the disposition of nebivolol among Chinese healthy subjects.
奈必洛尔是一种临床上重要的抗高血压药物，主要通过细胞色素P450（CYP）2D6代谢，其药代动力学存在广泛的个体间差异。CYP2D610等位基因（100C>T；rs1065852）在中国人群中高频存在，与许多药物的药代动力学改变有关，但其对奈必洛尔药代动力学的影响尚不清楚。本研究的目的是调查中国受试者中CYP2D610基因型和表型是否与奈必洛尔药代动力学变化相关。
24名健康受试者根据CYP2D6*1/1（n = 7）、CYP2D61/10（n = 5）和CYP2D610/*10（n = 12）基因型分为三组。*1/1纯合子和1/*10杂合子是C等位基因携带者。所有受试者口服单剂量奈必洛尔和右美沙芬。在不同时间采集血样和尿样。
三种CYP2D610基因型之间奈必洛尔的药代动力学无统计学显著差异，也未观察到基因剂量效应。CYP2D610/10受试者的药代动力学参数也与CYP2D61携带者相似。发现CYP2D6表型与奈必洛尔清除率之间存在弱相关性。
CYP2D610基因型和表型与奈必洛尔药代动力学的显著改变无关。单独的CYP2D610不能解释中国健康受试者中奈必洛尔处置过程中观察到的个体间巨大差异。
