Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats

The pharmacokinetics, tissue distribution, metabolism, and excretion of cel ecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenes ulfonamide, a cyclooxygenase-2 inhibitor, were investigated in rats. Celeco xib was metabolized extensively after i.v. administration of [C-14]celecoxi b, and elimination of unchanged compound was minor (less than 2%) in male a nd female rats. The only metabolism of celecoxib observed in rats was via a single oxidative pathway. The methyl group of celecoxib is first oxidized to a hydroxymethyl metabolite, followed by additional oxidation of the hydr oxymethyl group to a carboxylic acid metabolite. Glucuronide conjugates of both the hydroxymethyl and carboxylic acid metabolites are formed. Total me an percent recovery of the radioactive dose was about 100% for both the mal e rat (9.6% in urine; 91.7% in feces) and the female rat (10.6% in urine; 9 1.3% in feces). After oral administration of [C-14]celecoxib at doses of 20 , 80, and 400 mg/kg, the majority of the radioactivity was excreted in the feces (88-94%) with the remainder of the dose excreted in the urine (7-10%) . Both unchanged drug and the carboxylic acid metabolite of celecoxib were the major radioactive components excreted with the amount of celecoxib excr eted in the feces increasing with dose. When administered orally, celecoxib was well distributed to the tissues examined with the highest concentratio ns of radioactivity found in the gastrointestinal tract. Maximal concentrat ion of radioactivity was reached in most all tissues between 1 and 3 h post dose with the half-life paralleling that of plasma, with the exception of t he gastrointestinal tract tissues.