Catalytic roles of CYP2C9 and its variants (CYP2C9*2 and CYP2C9*3) in lornoxicam 5'-hydroxylation

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Izumi IidaK Chiba

Abstract

The effects of allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) on lornoxicam 5'-hydroxylation were studied using the corresponding variant protein expressed in baculovirus-infected insect cells and human liver microsomes of known genotypes of CYP2C9. The results of the baculovirus expression system showed that CYP2C9.3 gives higher K(m) and lower V(max) values for lornoxicam 5'-hydroxylation than does CYP2C9.1. In contrast, K(m) and V(max) values of CYP2C9.1 and CYP2C9.2 for the reaction were comparable. Lornoxicam 5'-hydroxylation was also determined in liver microsomes of 12 humans genotyped for the CYP2C9 gene (*1/*1, n = 7; *1/*2, n = 2; *1/*3, n = 2; *3/*3, n = 1). A sample genotyped as *3/*3 exhibited 8- to 50-fold lower intrinsic clearance for lornoxicam 5'-hydroxylation than did samples genotyped as *1/*1. However, the values for intrinsic clearance for *1/*3 were within the range of values exhibited by samples of *1/*1. In addition, no appreciable differences were observed in kinetic parameters for lornoxicam 5'-hydroxylation between *1/*1 and *1/*2. In conclusion, this study showed that lornoxicam 5'-hydroxylation via CYP2C9 was markedly decreased by the substitution of Ile359Leu (CYP2C9.3), whereas the effect of t...Continue Reading

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Citations

Dec 21, 2004·British Journal of Clinical Pharmacology·Yifan ZhangHui Zhou
Aug 10, 2007·Molecular Pharmacology·Lian WeiTimothy S Tracy
Jul 4, 2008·Pharmacogenomics·Victoria RollasonJules Desmeules
Jun 12, 2009·Drug Metabolism Reviews·Shu-Feng ZhouBalram Chowbay
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Apr 28, 2005·Drug Metabolism and Pharmacokinetics·Minoru Tsuda-TsukimotoToshiyuki Kume
Aug 22, 2006·Bone·M MousnyM D Grynpas
May 13, 2011·Journal of Molecular Modeling·M Ramesh, Prasad V Bharatam
Aug 25, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·A David Rodrigues
Mar 15, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yingjie GuoHui Zhou
Dec 1, 2004·Personalized Medicine·Julia KirchheinerJürgen Brockmöller
Dec 3, 2020·Drug Design, Development and Therapy·Peng-Fei TangGuo-Xin Hu

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