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

doi:10.5246/jcps.2018.01.002

Abstract

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 fragmentlength polymorphism (PCR-RFLP) assay. A pharmacokinetic study was then carried out in two groups with CYP2C9*1/*1 (n = 8) andCYP2C9*1/*2 (n = 6) genotypes at the same time, and all the 14 subjects were CYP3A4 wildgenotype. 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 (AUC_0–24), area under the curve from 0 h to infinite time (AUC_0–∞), peak plasma concentration (C_max), time to reach C_max (t_max), oral clearance (CL), oral volume of distribution (V_d) and elimination half-life (t_1/2), were determined. Compared with the CYP2C9*1/*2 group, the AUC₀_–24, AUC_0–∞ and C_max 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 itmight decrease the generationof E-3174. However, large-sample clinical trials are required to validate whether the dose adjustment according to CYP2C9 genotype is necessary.

Key words: Losaran, E-3174, CYP2C9*2, Pharmacokinetics, Hui

CLC Number:

R969.1

Supporting:

Lu Yang, Tao Guo, Xuemei Zhuang, Hongyan Gu. 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[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(1): 14-21.

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