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Vol. 293, Issue 2, 453-459, May 2000
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
In vitro studies were conducted to identify the cytochromes P450 (CYP)
involved in the oxidative metabolism of celecoxib. The hydroxylation of
celecoxib conformed to monophasic Michaelis-Menten kinetics (mean ± S.D., n = 4 livers,
Km = 3.8 ± 0.95 µM,
Vmax = 0.70 ± 0.45 nmol/min/mg
protein) in the presence of human liver microsomes, although substrate
inhibition was significant at higher celecoxib concentrations. The
treatment of a panel of human liver microsomal samples
(n = 16 subjects) with antibodies against CYP2C9 and CYP3A4 inhibited the formation of hydroxy celecoxib by 72 to 92%
and 0 to 27%, respectively. The presence of both antibodies in the
incubation suppressed the activity by 90 to 94%. In addition, the
formation of hydroxy celecoxib significantly correlated with CYP2C9-selective tolbutamide methyl hydroxylation
(r = 0.92, P < .001) and
CYP3A-selective testosterone 6
-hydroxylation (r = 0.55, P < .02). In contrast, correlation with
activities selective for other forms of CYP was weak
(r 
0.46). Chemical inhibition studies showed
that ketoconazole (selective for CYP3A4) and sulfaphenazole (selective
for CYP2C9) inhibited the formation of hydroxy celecoxib in a
concentration-dependent manner, whereas potent inhibitors selective for
other forms of CYP did not show any significant effect over a range of
1 to 10 µM. In agreement, cDNA-expressed CYP2C9 catalyzed the
formation of hydroxy celecoxib with an apparent Km value (µM) and a
Vmax value (pmol/min/pmol recombinant CYP) of 5.9 and 21.7, whereas a higher Km value
(18.2) and a lower Vmax value (1.42) were
obtained with rCYP3A4. It is concluded that methyl hydroxylation of
celecoxib is primarily catalyzed by human liver microsomal CYP2C9,
although CYP3A4 also plays a role.
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