细胞色素P450 2C19基因多态性对雷贝拉唑药动学和药效学的影响

目的研究中国汉族人细胞色素P450(CYP)2C19基因多态性及其对雷贝拉唑药动学和药效学的影响。方法在110例中国汉族健康志愿者中,应用聚合酶链反应限制性片段长度多态性(PCRRFLP)的方法确定CYP2C19基因型,分为纯合子强代谢型、杂合子强代谢型和弱代谢型3种表现型。从中分层选择20例幽门螺杆菌感染阴性的受试者,口服雷贝拉唑20mg/d×8d。分别在服药后第1天(d1)和第8天(d8)应用高效液相色谱法测定雷贝拉唑血药浓度,采用24h胃内pH监测仪分析雷贝拉唑的抑酸效果。结果CYP2C19弱代谢型占11%。服用雷贝拉唑d1时的血药浓度时间曲线下面积(AUC)在纯合子强代谢型、杂合子强代谢型和弱代谢型间的比率为1.0、1.3和1.8;给药d8时的AUC在这三种基因型间的比率为1.0、1.1和1.7。同时监测和分析24h胃内pH>4的总时间、24hpH>4的时间百分比、24h胃内pH中位值和均值,这些参数在CYP2C19三种基因型间均差异无显著性。服用雷贝拉唑d1和d8的24h胃内pH监测的各参数比例(d1/d8)在85%～110%之间。结论中国汉族人中,CYP2C19基因多态性对雷贝拉唑的药动学和药效学无明显影响。雷贝拉唑抑酸作用迅速。

Effects of cytochrome P450 2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of rabeprazole in Chinese

Objective To investigate whether the pharmacodynamics and pharmacokinetics of rabeprazole are dependent on the cytochrome P450(CYP)2C19 genotype status in Chinese Han healthy people. Methods The CYP 2C19 genotype status of 110 Chinese healthy volunteers was determined by polymerase chain reaction restriction fragment length polymorphism method. Twenty healthy subjects were voluntary to participate in the study. All subjects were Helicobacter pylori negative, which were determined by serology and 13 C urea breath test. After orally received rabeprazole 20 mg once daily in the morning for 8 d, the intragastric pH values were monitored for 24 h by Digitrapper pH on day 1 and day 8. Meanwhile, blood samples were collected at various time point until 24 h after administration. The serum concentrations of rabeprazole were measured by high performance liquid chromatography (HPLC). Results Of the 110 Chinese healthy subjects, the frequency of the poor metabolizer of CYP 2C19 was 11%. Of 20 volunteers received rabeprazole, there were seven homozygous extensive metabolisers(homEM), six heterozygous extensive metabolisers(hetEM) and seven poor metabolisers(PM). The mean area under concentration time curve(AUC) values for rabeprazole after a single dose differed among the three different genotype groups, with a relative ratio of 1.0, 1.3 and 1.8 in the homEM, hetEM and PM groups, respectively. After repeated doses, the mean AUC values for rabeprazole differed with a relative ratio of 1.0, 1.1 and 1.7 in the homEM, hetEM and PM groups, respectively. No significant differences in intragastric mean pH values, median, the total time of pH>4 and the pH>4 time percentage of 24 h were observed among the three different genotype groups after a single dose or repeated doses of rabeprazole. And the ratio of these pH dates between day 1 and day 8 ranged from 85% to 110%.Conclusions In Chinese healthy Han people, CYP 2C19 genetic polymorphism has not any significant influence on acid inhibitory efficacy and the metabolism of rabeprazole. Rebeprazole could rapidly achieved maximum acid inhibitory efficacy in the subjects with different CYP2 C19 genotype status.