Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites.

In-vitro data indicate major effects of the genetically polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) on the pharmacokinetics of celecoxib, a nonsteroidal anti-inflammatory drug acting as selective cyclooxygenase-2 inhibitor. Human studies report decreased clearance in heterozygous carriers of the CYP2C9 variant Ile359Leu (*3), but results appeared controversial and only data on single subjects carrying the homozygous CYP2C9*3/*3 genotype have been published. We measured single-dose kinetics of celecoxib and its main metabolites hydroxy- and carboxy-celecoxib in 21 healthy volunteers who were selected as hetero- (n = 4) and homozygous (n = 3) carriers of CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Blood concentrations of celecoxib and its metabolites hydroxy-celecoxib and carboxy-celecoxib were quantified by high-performance liquid chromatography. A more than two-fold reduced oral clearance in homozygous carriers of CYP2C9*3 was seen for celecoxib compared to carriers of the wild-type genotype CYP2C9*1/*1 and heterozygous carriers of one *3 allele were in-between (P = 0.003 for trend), whereas CYP2C9*2 had no significant influence on celecoxib pharmacokinetics. Decreased concentrations of carboxy- and hydroxy-celecoxib in heterozygous and homozygous carriers of CYP2C9*3 were detected which supported the influence of CYP2C9 polymorphisms on celecoxib pharmacokinetic variability. Approximately 0.5% of Caucasians carrying the genotype CYP2C9*3/*3 will have greatly increased internal exposure to celecoxib. It remains to be shown whether this is associated with greater efficacy or with an increased incidence and severity of adverse events.