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Vol. 30, Issue 4, 385-390, April 2002
Deparment of Basic Pharmaceutical Sciences, School of Pharmacy,
West Virginia University, Morgantown, West Virginia (T.S.T., J.M.H.,
M.A.H.); Department of Medicinal Chemistry, School of Pharmacy,
University of Washington, Seattle, Washington (R.L.H., A.E.R., L.J.D.)
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. The F114L mutant exhibited a hyperbolic kinetic profile for
flurbiprofen metabolism, a linear profile for naproxen metabolism, and
a substrate inhibition kinetic profile for piroxicam metabolism. In all
cases except F114L-mediated piroxicam metabolism, turnover decreased and the Km generally increased for each
allelic variant compared with wild-type enzyme. It seems that the
kinetic profile of CYP2C9-mediated metabolism is dependent on both
substrate and the CYP2C9 allelic variant, thus having potential
ramifications on drug disposition predictions made during the
development process.
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