Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans

CYP2C9 is an important member of the cytochrome P450 enzyme superfamily with some 12 CYP2C9 alleles (* 1-* 12) being previously reported. Recently, we identified a new CYP2C9 allele with a Leu90Pro mutation in a Chinese poor metabolizer of lornoxicam [ Si D, Guo Y, Zhang Y, Yang L, Zhou H, and Zhong D ( 2004) Pharmacogenetics 14: 465 - 469]. The new allele, designated CYP2C9*13, was found to occur in approximately 2% of the Chinese population. To examine enzymatic activity of the CYP2C9*13 allele, kinetic parameters for lornoxicam 5'-hydroxylation were determined in COS-7 cells transiently transfected with pcDNA3.1 plasmids carrying wild-type CYP2C9*1, variant CYP2C9*3, and CYP2C9*13 cDNA. The protein levels of cDNA-expressed CYP2C9*3 and * 13 in postmitochondrial supernatant (S9) from transfected cells were lower than those from wild-type CYP2C9*1. Mean values of Km and V-max for CYP2C9*1, * 3, and * 13 were 1.24, 1.61, and 2.79 mu M and 0.83, 0.28, and 0.22 pmol/min/pmol, respectively. Intrinsic clearance values (V-max/K-m) for variant CYP2C9*3 and CYP2C9*13 on the basis of CYP2C9 protein levels were separately decreased to 28% and 12% compared with wild type. In a subsequent clinical study, the AUC of lornoxicam was increased by 1.9-fold and its oral clearance (CL/F) decreased by 44% in three CYP2C9*1/*13 subjects, compared with CYP2C9*1/*1 individuals. This suggests that the CYP2C9*13 allele is associated with decreased enzymatic activity both in vitro and in vivo.