The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. ...The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.展开更多
In the present study,we aimed to investigate the influence of CYP2C9^＊2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chine...In the present study,we aimed to investigate the influence of CYP2C9^＊2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects.Blood samples were collected from subjects for CYP2C9 and CYP3A4 genotyping using a polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） assay.A pharmacokinetic study was then carried out in two groups with CYP2 C9^＊1/^＊1（n = 8） and CYP2 C9^＊1/^＊2（n = 6） genotypes at the same time,and all the 14 subjects were CYP3A4 wild genotype.Plasma levels of losartan and E-3174 were determined by high-performance liquid chromatography-fluorescence（HPLC-FLD） method before and after a single oral dose of 50-mg dose of losartan in tablet form.The pharmacokinetic parameters were calculated by DAS 2.0 software and analyzed by SPSS 16.0 software.Pharmacokinetic parameters,including area under the curve from 0 h to the last measured point 24 h（AUC0–24）,area under the curve from 0 h to infinite time（AUC0–∞）,peak plasma concentration（Cmax）,time to reach Cmax（tmax）,oral clearance（CL）,oral volume of distribution（Vd） and elimination half-life（t1/2）,were determined.Compared with the CYP2C9^＊1/^＊2 group,the AUC0–24,AUC0–∞ and Cmax of E-3174 in CYP2C9^＊1/^＊1 group of Hui subjects were respectively 1.36,1.32 and 1.64 times more,and the statistic differences were significant（P〈0.05）.The CYP2C9^＊2 mutant allele played an important role in the pharmacokinetics of losartan after oral administration,and it might decrease the generation of E-3174.However,large-sample clinical trials are required to validate whether the dose adjustment according to CYP2C9 genotype is necessary.展开更多
基金The 115th Project of Legionary Medical Treatment and Public Health(Grant No.06G023)
文摘The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.
基金A Research Grant from the 115 Project of Legionary Medical Treatment and Public Health(Grant No.06G023)
文摘In the present study,we aimed to investigate the influence of CYP2C9^＊2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects.Blood samples were collected from subjects for CYP2C9 and CYP3A4 genotyping using a polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） assay.A pharmacokinetic study was then carried out in two groups with CYP2 C9^＊1/^＊1（n = 8） and CYP2 C9^＊1/^＊2（n = 6） genotypes at the same time,and all the 14 subjects were CYP3A4 wild genotype.Plasma levels of losartan and E-3174 were determined by high-performance liquid chromatography-fluorescence（HPLC-FLD） method before and after a single oral dose of 50-mg dose of losartan in tablet form.The pharmacokinetic parameters were calculated by DAS 2.0 software and analyzed by SPSS 16.0 software.Pharmacokinetic parameters,including area under the curve from 0 h to the last measured point 24 h（AUC0–24）,area under the curve from 0 h to infinite time（AUC0–∞）,peak plasma concentration（Cmax）,time to reach Cmax（tmax）,oral clearance（CL）,oral volume of distribution（Vd） and elimination half-life（t1/2）,were determined.Compared with the CYP2C9^＊1/^＊2 group,the AUC0–24,AUC0–∞ and Cmax of E-3174 in CYP2C9^＊1/^＊1 group of Hui subjects were respectively 1.36,1.32 and 1.64 times more,and the statistic differences were significant（P〈0.05）.The CYP2C9^＊2 mutant allele played an important role in the pharmacokinetics of losartan after oral administration,and it might decrease the generation of E-3174.However,large-sample clinical trials are required to validate whether the dose adjustment according to CYP2C9 genotype is necessary.
