Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite.

Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for the treatment of rheumatoid arthritis and osteoarthritis. The predominant hepatic metabolism of celecoxib to celecoxib carboxylic acid (CCA) is mediated mainly by CYP2C9. We investigated the effects of the major CYP2C9 genetic variants in Asian populations, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in healthy Korean subjects. A single 200-mg oral dose of celecoxib was given to 52 Korean subjects with different CYP2C9 genotypes: CYP2C9EM (n = 26; CYP2C9*1/*1), CYP2C9IM (n = 24; CYP2C9*1/*3 and *1/*13), and CYP2C9PM (n = 2; CYP2C9*3/*3). Celecoxib and CCA concentrations in plasma samples collected up to 48 or 96 h after drug intake were determined by HPLC-MS/MS. The mean area under the plasma concentration-time curve (AUC0-∞) of celecoxib was increased 1.63-fold (P < 0.001), and the apparent oral clearance (CL/F) of celecoxib was decreased by 39.6% in the CYP2C9IM genotype group compared with that of CYP2C9EM (P < 0.001). The overall pharmacokinetic parameters for celecoxib in CYP2C9*1/*13 subjects were similar to those in CYP2C9*1/*3 subjects. Two subjects with CYP2C9PM genotype both showed markedly higher AUC0-∞, prolonged half-life, and lower CL/F for celecoxib than did subjects with CYP2C9EM and IM genotypes. CYP2C9*3 and CYP2C9*13 variant alleles significantly affected the plasma concentration of celecoxib.