Abstract
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.
Published Version
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