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Vol. 293, Issue 2, 453-459, May 2000

Major Role of Human Liver Microsomal Cytochrome P450 2C9 (CYP2C9) in the Oxidative Metabolism of Celecoxib, a Novel Cyclooxygenase-II Inhibitor

Cuyue Tang, Magang Shou, Qin Mei, Thomas H. Rushmore and A. David Rodrigues

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 6beta -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.

0022-3565/00/2932-0453$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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