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Drug Metabolism and Disposition Fast Forward
First published on March 11, 2005; DOI: 10.1124/dmd.105.003616

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Received for publication January 10, 2005.
Revised March 9, 2005.
Accepted for publication March 9, 2005.

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

Yingjie Guo 1, Yifan Zhang 2, Ying Wang 1, Xiaoyan Chen 2, Dayong Si 1, Dafang Zhong 2, J Paul Fawcett 3, Hui Zhou 1*

1 College of life Science, Jilin University, Changchun, China 2 Laboratory of Drug metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang, Ch 3 School of Pharmacy University of Otago, Dunedin, New Zealand

* Address correspondence to: E-mail: zhouhui{at}mail.jlu.edu.cn

Abstract

CYP2C9 is an important member of the cytochrome P450 enzyme superfamily with some twelve 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 et al., 2004). 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 from wild-type CYP2C9*1. Mean values of Km and Vmax for CYP2C9*1, *3 and *13 were 1.24, 1.61 and 2.79 µg and 0.83, 0.28 and 0.22 pmol/min/pmol, respectively. Intrinsic clearance values (Vmax/Km) 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 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.


Key words: CYP expression, cytochrome P450 isoforms, enzyme kinetics, HPLC, human CYP enzymes, mutagenesis, non-steroidal anti-inflammatory drugs, pharmacogenetics, recombinant proteins, site-directed mutagenesis


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