PMID: 11901091Mar 20, 2002Paper

Polymorphic variants (CYP2C9*3 and CYP2C9*5) and the F114L active site mutation of CYP2C9: effect on atypical kinetic metabolism profiles

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Timothy S TracyLeslie J Dickmann

Abstract

CYP2C9 wild-type protein has been shown to exhibit atypical kinetic profiles of metabolism that may affect in vitro-in vivo predictions made during the drug development process. Previous work suggests a substrate-dependent effect of polymorphic variants of CYP2C9 on the rate of metabolism; however, it is hypothesized that these active site amino acid changes will affect the kinetic profile of a drug's metabolism as well. To this end, the kinetic profiles of three model CYP2C9 substrates (flurbiprofen, naproxen, and piroxicam) were studied using purified CYP2C9*1 (wild-type) and variants involving active site amino acid changes, including the naturally occurring variants CYP2C9*3 (Leu359) and CYP2C9*5 (Glu360) and the man-made mutant CYP2C9 F114L. CYP2C9*1 (wild-type) metabolized each of the three compounds with a distinctive profile reflective of typical hyperbolic (flurbiprofen), biphasic (naproxen), and substrate inhibition (piroxicam) kinetics. CYP2C9*3 metabolism was again hyperbolic for flurbiprofen, of a linear form for naproxen (no saturation noted), and exhibited substrate inhibition with piroxicam. CYP2C9*5-mediated metabolism was hyperbolic for flurbiprofen and piroxicam but linear with respect to naproxen turnover. T...Continue Reading

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Citations

Jul 19, 2005·European Journal of Clinical Pharmacology·Jónrit HallingKim Brøsen
Nov 13, 2013·Medicina clínica·Ana M Peiró Peiró
Apr 8, 2011·Analytical Chemistry·Andrea FantuzziGianfranco Gilardi
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Apr 21, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Charles W LocusonTimothy S Tracy
May 19, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Murali SubramanianTimothy S Tracy
Mar 11, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Murali SubramanianTimothy S Tracy
Dec 30, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Darcy R Flora, Timothy S Tracy
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