In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelicvariant forms of human liver microsomal cytochrome P4502C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics

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 cDN A-expressed wild-type CYP2C9 (CYP2C9*1), the V-max/K-m ratio for celecoxib methyl hydroxylation tvas reduced by 34% and 90% in the presence of recombi nant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the ami no acid substitution at position 359 (Ile to Leu) elicited a more pronounce d effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The V-max/K-m 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 re flective of a decrease in V-max, with a minimal change in K-m. Based on sim ulations 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 sub jects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (C ys(144)) or CYP2C9*3 (Leu(359)) 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, t here was no significant change in celecoxib AUC in two subjects genotyped C YP2C9*1/*2, Pharmacogenetics 11:223-235 (C) 2001 Lippincott Williams & Wilk ins.