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建立氯沙坦及其活性代谢物E-3174在中国不同民族中的群体药代动力学模型,为临床个体化用药提供参考。采用HPLC荧光法同时测定氯沙坦及E-3174的血药浓度。应用非线性混合效应模型法(nonlinear mixed-effect modeling,NONMEM),分别尝试单室、二室和三室模型拟合来自50个中国健康受试者(包括汉族、蒙古族、朝鲜族、回族和维吾尔族)的血浆药物浓度-时间数据。采用正向模型化和逆向剔除的方法逐一考查了人口统计学和生化指标对氯沙坦基础模型的影响。氯沙坦的最终模型和E-3174间采用一级动力学或转运隔室模型进行连接。在组合模型中对氯沙坦及其活性代谢物E-3174的药物动力学参数进行拟合,考察协变量对E-3174关键药代动力学参数的影响。非参数bootstrap法对模型的稳定性进行验证。线性消除的二室模型可较好拟合氯沙坦的数据。氯沙坦及其代谢物E-3174达峰时间分别为0.9和3.8小时。两个转运隔室可准确拟合E-3174滞后的达峰时间。群体拟合结果显示约有73.9%的氯沙坦转化为E-3174。民族因素能显著影响氯沙坦的清除率CL10、隔室间清除率CL2和中心室的表观分布容积V1以及氯沙坦向E-3174的转运速率常数(Kt)。1000次的bootstrap中有925次收敛成功。群体药代动力学模型经过验证稳定可靠。民族因素显著影响氯沙坦的清除率和氯沙坦向E-3174的转化,E-3174的药代动力学参数不受任何因素的影响。
To establish a population pharmacokinetic model of losartan and its active metabolite E-3174 in different ethnic groups in China, and to provide a reference for clinical individualized drug use. The plasma concentrations of losartan and E-3174 were determined simultaneously by HPLC fluorescence spectrometry. Using nonlinear mixed-effect modeling (NONMEM), single-chamber, two-chamber and three-chamber models were tried to fit the data from 50 Chinese healthy subjects (including Han, Mongolian, Korean, Hui and Uyghur Family) plasma drug concentration-time data. The effects of demographic and biochemical parameters on losartan basic model were examined one by one using forward modeling and reverse culling. The final model of losartan is connected to E-3174 using a first-order kinetic or transport compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were fitted in a combined model to investigate the effect of covariates on key pharmacokinetic parameters of E-3174. Nonparametric bootstrap method is used to verify the stability of the model. A two-compartment model of linear elimination fits well to losartan data. Losartan and its metabolite E-3174 peaked at 0.9 and 3.8 hours, respectively. The two transfer compartments accurately fit the peak time of the E-3174 lag. Population fit results showed that about 73.9% of losartan was converted to E-3174. National factors can significantly affect the clearance rate of losartan CL10, clearance between compartments CL2 and the central ventricular apparent distribution volume V1 and Losartan to E-3174 transport rate constant (Kt). There are 925 convergence successes in 1000 bootstrap. Population pharmacokinetic models have been verified to be stable and reliable. National factors significantly affected losartan clearance and conversion of losartan to E-3174, and the pharmacokinetic parameters of E-3174 were unaffected by any factors.