PT  - JOURNAL ARTICLE
AU  - Hu, Guo-Xin
AU  - Pan, Pei-Pei
AU  - Wang, Zeng-Shou
AU  - Yang, Li-Ping
AU  - Dai, Da-Peng
AU  - Wang, Shuang-Hu
AU  - Zhu, Guang-Hui
AU  - Qiu, Xiang-Jun
AU  - Xu, Tao
AU  - Luo, Jun
AU  - Lian, Qing-Quan
AU  - Ge, Ren-Shan
AU  - Cai, Jian-Ping
TI  - In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population
AID  - 10.1124/dmd.114.061200
DP  - 2015 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 561--569
VI  - 43
IP  - 4
4099  - http://dmd.aspetjournals.org/content/43/4/561.short
4100  - http://dmd.aspetjournals.org/content/43/4/561.full
SO  - Drug Metab Dispos2015 Apr 01; 43
AB  - Our previous study detected totally 35 CYP2C9 allelic 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 CYP2C9 allelic variants both in vitro and in vivo. Different types of CYP2C9 variants 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/*1 wild-type subjects, subjects with *1/*40 genotype 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/*48 genotype exhibited significantly decreased CL/F, and those with *1/*27, *1/*29, *1/*40, and *1/*41 genotype presented similar CL/F value. When expressed in COS-7 cells, the CYP2C9 variants showed similar pattern to the results in clinical study. The study suggests that, besides two typical defective alleles, *3 and *13, seven CYP2C9 allelic 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.