Li Z, Wang G, Wang L-S, Zhang W, Tan Z-R, Fan L, Chen B-L, Li Q, Liu J, Tu J-H, Hu D-L, Liu Z-Q, Zhou H-H
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, P. R. China.
Xenobiotica. 2009 Oct;39(10):788-93. doi: 10.1080/00498250903134435.
The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C913 allele. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C91/1, n = 6; CYP2C91/13, n = 4; and CYP2C91/3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C913 and 13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy-Weinberg equilibrium. Compared with the subjects in the CYP2C91/1 group, individuals carrying the CYP2C91/13 genotype showed significantly a longer t(1/2) of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C91/3 genotype group had significant differences in t(1/2) and Cmax of E3174 compared with the CYP2C91/1 group. The ratio of AUC(E3174)/AUC(losartan) after losartan administration in the CYP2C91/13 and CYP2C91/3 groups was also statistically different from that in the CYP2C91/1 group. The data indicate that the presence of the CYP2C913 allele results in poor metabolism of losartan after a single oral dose.
本研究的目的是确定氯沙坦与CYP2C913等位基因相关的药代动力学。对16名具有不同基因型（CYP2C91/1，n = 6；CYP2C91/13，n = 4；CYP2C91/3，n = 6）的健康男性志愿者每人单次口服50mg氯沙坦。在给药前至给药后24小时采集血样。采用液相色谱-串联质谱法（LC-MS/MS）测定血浆氯沙坦和E3174（氯沙坦的活性代谢产物）。所有受试者均完成研究，未出现药物不良反应。在本研究中，中国健康志愿者中CYP2C913和13等位基因的频率分别为0.6%和2.6%，且两个等位基因均处于哈迪-温伯格平衡状态。与CYP2C91/1组的受试者相比，携带CYP2C91/13基因型的个体氯沙坦和E3174的t(1/2)显著延长，氯沙坦的曲线下面积（AUC）明显增加。同时，CYP2C91/3基因型组与CYP2C91/1组相比，E3174的t(1/2)和Cmax存在显著差异。氯沙坦给药后，CYP2C91/13组和CYP2C91/3组中AUC(E3174)/AUC(氯沙坦)的比值与CYP2C91/1组相比也有统计学差异。数据表明，CYP2C913等位基因的存在导致单次口服氯沙坦后代谢不良。
