In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population

Cytochrome P450 2C9 (CYP2C9) is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Recently, we identified 22 novel alleles (*36 -*56 and N418T) in the Han Chinese population. This study aims to assess the catalytic activities of wildtype (CYP2C9*1) and 36 CYP2C9 allelic variants found in the Chinese population toward phenytoin (PHT) in vitro. Insect microsomes expressing CYP2C9*1 and 36 CYP2C9 variants were incubated with 1-200 mu M phenytoin for 30 min at 37 degrees C. Then, these products were extracted and the signal detection was performed by HPLC-MS/MS. The intrinsic clearance (V-max/K-m) values of all variants, with the exception of CYP2C9*2, CYP2C9*11, CYP2C9*23, CYP2C9*29, CYP2C9*34, CYP2C9*38, CYP2C9*44, CYP2C9*46 and CYP2C9*48, were significantly different from CYP2C9*1. CYP2C9* 27, *40, *41, *47, *49, *51, *53, *54, *56 and N418T variant exhibited markedly larger values than CYP2C9*1 (> 152.8%), whereas 17 variants exhibited smaller values (from 48.6% to 99.9%) due to larger K-m and/or smaller V-max values than CYP2C9*1. The findings suggest that more attention should be paid on subjects carrying these infrequent CYP2C9 alleles when administering phenytoin in clinic. (C) 2016 Elsevier Ireland Ltd. All rights reserved.