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In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

Authors :
Hu, Guo-Xin
Pan, Pei-Pei
Wang, Zeng-Shou
Yang, Li-Ping
Dai, Da-Peng
Wang, Shuang-Hu
Zhu, Guang-Hui
Qiu, Xiang-Jun
Xu, Tao
Luo, Jun
Lian, Qing-Quan
Ge, Ren-Shan
Cai, Jian-Ping
Source :
Drug Metabolism and Disposition; 2015, Vol. 43 Issue: 4 p561-569, 9p
Publication Year :
2015

Abstract

Our previous study detected totally 35 CYP2C9allelic variants in 2127 Chinese subjects, of whom 21 novel alleles were reported for the first time in Chinese populations. The aim of the present study was to characterize the 13 CYP2C9allelic variants both in vitro and in vivo. Different types of CYP2C9variants were highly expressed in COS-7 cells, and 50 μM tolbutamide was added as the probing substrate to evaluate their metabolic abilities in vitro. Subsequently, the concentrations of tolbutamide and its metabolite in the plasma and urine within individuals with different types of genotypes were determined by HPLC to evaluate the catalytic activity of the 13 mutant CYP2C9 proteins in vivo. Our results showed that compared with *1/*1wild-type subjects, subjects with *1/*40genotype showed increased oral clearance (CL/F), whereas individuals with *1/*3, *1/*13, *3/*3, *3/*13, *1/*16, *1/*19, *1/*34, *1/*42, *1/*45, *1/*46, and *1/*48genotype exhibited significantly decreased CL/F, and those with *1/*27, *1/*29, *1/*40,and *1/*41genotype presented similar CL/F value. When expressed in COS-7 cells, the CYP2C9variants showed similar pattern to the results in clinical study. The study suggests that, besides two typical defective alleles, *3and *13, seven CYP2C9allelic variants (*16, *19, *34, *42, *45, *46, and *48) cause defective effects on the enzymatic activities both in vitro and in vivo. In clinic, patients with these defective alleles should be paid close attention to.

Details

Language :
English
ISSN :
00909556 and 1521009X
Volume :
43
Issue :
4
Database :
Supplemental Index
Journal :
Drug Metabolism and Disposition
Publication Type :
Periodical
Accession number :
ejs35174583
Full Text :
https://doi.org/10.1124/dmd.114.061200