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ROLE OF CYP2C9 AND ITS VARIANTS (CYP2C9^*3 AND CYP2C9^*13) IN THE METABOLISM OF LORNOXICAM IN HUMANS

College of Life Science, Jilin University, Changchun, China (Y.G., Y.W., D.S., H.Z.); Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang, China (Y.Z., X.C., D.Z.); and School of Pharmacy, University of Otago, Dunedin, New Zealand (J.P.F.)

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 K_m and V_max for CYP2C9^*1, ^*3, and ^*13 were 1.24, 1.61, and 2.79 µM 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.

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