Chen B L, Chen Y, Tu J H, Li Y L, Zhang W, Li Q, Fan L, Tan Z R, Hu D L, Wang D, Wang L S, Ouyang D S, Zhou H H
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology Central South University, Changsha, Hunan, PR China.
J Clin Pharmacol. 2009 May;49(5):574-81. doi: 10.1177/0091270009333016.
This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/1, 5 CYP2C192/2, and 1 CYP2C192/3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C191/1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C191/1. No significant alteration is observed in CYP2C192/*2 or 3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C191/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.
本研究探讨了氯吡格雷对与CYP2C19基因多态性相关的奥美拉唑药代动力学的影响。12名健康志愿者（6名CYP2C191/1、5名CYP2C192/2和1名CYP2C192/3）参与了一项两阶段随机交叉试验。在每个阶段，志愿者在接受安慰剂或氯吡格雷预处理（第一天300mg，然后连续3天每天75mg）后，口服单剂量40mg奥美拉唑。通过高效液相色谱-紫外检测法定量测定奥美拉唑及其代谢物的血浆浓度。氯吡格雷治疗后，CYP2C191/1中奥美拉唑的AUC(0-无穷大)增加30.02%±18.03%（P = .004），5-羟基奥美拉唑的AUC(0-无穷大)降低24.30%±11.66%（P = .032）。CYP2C191/1中奥美拉唑与5-羟基奥美拉唑的AUC(0-无穷大)比值增加74.98%±35.48%（P = .001），奥美拉唑与奥美拉唑砜的AUC(0-无穷大)比值无显著变化（P = .832）。在CYP2C192/2或3中未观察到显著改变。氯吡格雷抑制CYP2C191/*1中奥美拉唑的CYP2C19依赖性羟基化，对奥美拉唑的CYP3A4催化的硫氧化无影响。
