CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学的影响

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese volunteers

目的研究CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学的影响。方法在18例幽门螺杆菌感染阴性的健康志愿者中,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法确定CYP2C19基因型,分为纯合子强代谢型(homEM),杂合子强代谢型(hetEM)和弱代谢型(PM)3组,每组6人。受试者口服奥美拉唑20 mg.d-1,连续8 d。分别在服药后d 1和d 8,应用高效液相色谱法测定奥美拉唑血药浓度,采用24 h胃内pH监测仪监测胃内pH情况。结果服用奥美拉唑d1,PM组的血药浓度-时间曲线下面积(AUC)高于homEM组和hetEM组,在三种基因型之间的相对比率为1∶1.1∶4.2(homEM∶hetEM∶PM);在服药d 8,PM组的AUC值也高于homEM组和hetEM组,在三种基因型之间的相对比率为1.0∶1.3∶3.3(homEM∶hetEM∶PM)。在服药d1,24 h胃内pH中位值、pH>3的总时间和pH>4的总时间在三种基因型间差异有显著性;在服药d 8,这些参数在PM组高于其它两组。结论CYP2C19基因多态性对奥美拉唑在中国人体内的药物动力学和药效学有明显影响。

Aim To investigate whether the pharmaco- dynamics and pharmacokinetics of omeprazole are dependent on the CYP2C19 genotype status in Chinese volunteers. Methods Eighteen healthy subjects voluntcered to participate in the study, whose CYP2C19 genotype status were determined with polymerase chain reaction-restriction fragment length polymorphism method. There were six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers. All subjects were H. pylori-negative, which were determined with serology and 13C-urea breath test. After d 1 and d 8 oral administration of omeprazole 20 mg once daily in the morning, intragastric pH values were monitored for 24 h with Digitrapper pH. Meanwhile, blood samples were collected at various time-points until 24 h after the administration. The serum concentrations of omeprazole were measured with high performance liquid chromatography. Results After a single dose, the PMs showed a significantly higher mean AUC value than that of the homEMs or hetEMs, with a relative ratio of 1.0 ： 1.1 ： 4.2（homEM ： hetEM ： PM）;after repeated doses, the PMs also showed a significantly higher mean AUC value than that of the homEMs or hetEMs, with a relative ratio of 1.0 ： 1.3 ： 3.3（homEM ： hetEM ： PM）. After a single dose of omeprazole, significant differences in intragastric pH median, pH 〉 3 holding time and pH 〉 4 holding time were observed among the three groups. After repeated doses, the PMs showed a significantly higher intragastric pH value than that of the homEMs or hetEMs. Conclusion The pharmacodynamic effects of omeprazole and its pharmacokinetics depend on the CYP2C19 genotype status in Chinese volunteers.