title: Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites.
abstract: 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.
authors.affiliation: Institute of Clinical Pharmacology, Charité, Humboldt University of Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany. julia.kirchheiner@charite.de
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Elke
authors.initials: E
authors.lastname: Störmer
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Nadine
authors.initials: N
authors.lastname: Steinbach
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D011720:Pyrazoles; D012016:Reference Values; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000068579:Celecoxib