Effects of CYP2C9*3 and CYP2C9*13 alleles on the pharmacokinetics of celecoxib and its carboxylic metabolite

Purpose: Celecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor and is used for the treatment of rheumatoid arthritis and osteoarthritis. Celecoxib is mainly metabolized via hydroxylation pathway, which is primarily mediated by CYP2C9, and further immediately oxidized to the inactive carboxylic metabolite. We investigated effects of CYP2C9 genetic polymorphism on the pharmacokinetics of celecoxib and its metabolite in healthy Korean subjects.

Methods: Twenty-six subjects were selected and they were divided into three different groups according to CYP2C9 genotype, CYP2C9EM (CYP2C9*1/*1, n=12), CYP2C9IM (CYP2C19*1/*3 and CYP2C9*1/*13, n=12) and CYP2C9PM (CYP2C9*3/*3, n=2). After overnight fasting, each subject received a single oral dose of 200 mg celecoxib. Blood samples were collected up to 48 hr after drug intake, and plasma concentrations of celecoxib and its carboxylic metabolite were determined by using LC-MS/MS system.

Results: AUC_inf of celecoxib in CYP2C9IM group was significantly higher than that in CYP2C9EM group (P<0.001). Oral clearance (CL/F) of celecoxib in CYP2C9IM group was significantly lower than that in CYP2C9EM group (P<0.01). Other parameters of celecoxib were not significantly different between two groups. All pharmacokinetic parameters of celecoxib carboxylic acid (CCA) between CYP2C9EM and CYP2C9IM groups were not statistically significant. Marked increased plasma concentrations of celecoxib and decreased concentrations of CCA were observed in CYP2C9PM group compared with those in other genotype groups.

Conclusion: CYP2C9 genetic polymorphism can affect the pharmacokinetics of celecoxib and its carboxylic metabolite.