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In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics

Tang, Cuyuea; Shou, Maganga; Rushmore, Thomas H.a; Mei, Qina; Sandhu, Punama; Woolf, Eric J.a; Rose, Mark J.a; Gelmann, Alyssac; Greenberg, Howard E.c; De Lepeleire, Ingee; Van Hecken, Anned; De Schepper, Paul J.d; Ebel, David L.b; Schwartz, Jules I.b; Rodrigues, A. Davida

Original Article

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/ Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/ Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6–3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

aDrug Metabolism, Merck Research Laboratories, West Point, PA, USA, bClinical Pharmacology, Merck Research Laboratories, Rahway, NJ, USA, cDepartment of Medicine, Thomas Jefferson University, Philadelphia, PA, USA, dDepartment of Pharmacology, University of Leuven, School of Medicine, Leuven, Belgium and eClinical Pharmacology, Merck Research Laboratories, Brussels, Belgium

Received 3 July 2000; accepted 23 August 2000

Correspondence to Cuyue Tang, Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, WP75A-203, West Point, PA 19486, USA Tel: +1 215 652 9537; fax: +1 215 652 2410; e-mail:

© 2001 Lippincott Williams & Wilkins, Inc.