中国健康受试者口服奥美拉唑肠溶胶囊的群体药动学研究

摘要

目的 建立中国健康受试者口服奥美拉唑肠溶胶囊的群体药动学模型,定量考察影响奥美拉唑临床药动学的显著因素.方法 选取南京医科大学附属南京医院于2016年4～6月招募的20名中国男性健康受试者,单剂量给予奥美拉唑肠溶胶囊20 mg,LC-MS/MS法测定奥美拉唑血药浓度,聚合酶链式反应-限制性片段长度多态性法测定CYP2C19基因型,采用非线性混合效应模型法建立奥美拉唑群体药动学模型,自举法验证模型的稳定性.结果 奥美拉唑在健康受试者体内的药动学可用一级消除的一房室模型来描述,个体间变异符合指数模型.奥美拉唑清除率(CL/F)、分布容积(V/F)和吸收常数(Ka)的群体典型值分别为19.5 L/h、16 L和0.633/h.尿素氮对Ka有显著性影响,CYP2C19代谢表型对CL/F有显著性影响.自举法的验证结果与模型计算值相符.结论 所建立的群体药动学模型能较好的解释奥美拉唑药动学个体差异的原因,可为奥美拉唑临床个体化用药提供药动学参考.%Objective To establish population pharmacokinetics model of Omeprazole Enteric-Coated Capsules in Chinese healthy subjects,thus quantitatively evaluating the factors that could influence clinical pharmacokinetics of Omeprazole.Methods Twenty healthy male subjects recruited in Nanjing First Hospital from April 2016 to June 2016 were given 20 mg single dose of Omeprazole Enteric-Coated Capsules and plasma concentrations of the drug were determined by LC-MS/MS.CYP2C19 gene polymorphism was measured by polymerase chain reaction-restriction fragment length polymorphism method.The population pharmacokinetic model was established by nonlinear mixed effect model (NONMEM)program and estimated by bootstrap procedure.Results One-compartmen model of first-order elimination had fit for Omeprazole pharmacokinetics.Inter-individual variability was described by exponential model.The population typical values of CL/F,V/F and Ka were19.5L/h,16Land0.633/h.BUN had a significant influence on Ka.CYP2C19 phenotype showed significant effects on CL/F.The parameters estimated from bootstrap procedure were comparable to those from NONMEM.Conclusion The established population pharmacokinetics model can explain the individual pharmacokinetic variations of Omeprazole,which provides guidance for clinical personalized drug administration.