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

Abstract

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 (AUC) 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 AUC, 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.

Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer

“…Their metabolic pathways are similar to that of endogenous IgG, not go through the cytochrome P450 enzyme metabolic pathway. While celecoxib is mainly metabolized by CYP2C9 (50), so there might be no drug interaction between them theoretically. Secondly, we take Celecoxib, the most representative selective COX-2 inhibitor, as an example, to illustrate the side-effects of COX-2 inhibitor.…”

Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study

“…The influence of genetic polymorphisms on the metabolism of celecoxib is less clear. Celecoxib is primarily metabolised by CYP2C9 [19, 29], and while polymorphisms such as CYP2C9*3 have been reported to affect pharmacokinetics, including in Asian populations [16, 17], the clinical relevance of these findings is still subject to debate [29–31]. In the current study, some differences were seen in the pharmacokinetic exposure of tramadol and M1, although these were primarily accounted for by differences in body weight in the case of tramadol.…”

Oh wait … It isn’t MUDPILES! Acute toxic encephalopathy with an interesting anion gap metabolic acidosis resulting in prolonged invasive mechanical ventilation

“…Our patient had taken a significant amount of Celecoxib, resulting in a large anion gap initially as shown in (Table 1) with an elevated anion gap on admission. As Celecoxib underwent hepatic metabolism via CYP2C9, the anion gap decreased [4,5].…”