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.
