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Vol. 28, Issue 5, 514-521, May 2000
Departments of Clinical Pharmacokinetics and Bioavailability
(S.K.P.), Metabolism and Safety Evaluation (J.Y.Z., A.P.B., C.J.G.,
C.S.M., E.G.B.), Physical Methodology (J.D.H., N.W.K.L.), Regulatory
Affairs (S.M.J., Y.M.L.), and COX-2 Technology (T.J.M.), G.D. Searle & Co., Skokie, Illinois; and Nutrition and Consumer Products, Monsanto
Company, St. Louis, Missouri (J.N.C.)
The pharmacokinetics, tissue distribution, metabolism, and
excretion of celecoxib,
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, a cyclooxygenase-2 inhibitor, were investigated in
rats. Celecoxib was metabolized extensively after i.v. administration of [14C]celecoxib, and elimination of unchanged compound
was minor (less than 2%) in male and 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 hydroxymethyl group
to a carboxylic acid metabolite. Glucuronide conjugates of both the hydroxymethyl and carboxylic acid metabolites are formed. Total mean
percent recovery of the radioactive dose was about 100% for both the
male rat (9.6% in urine; 91.7% in feces) and the female rat (10.6%
in urine; 91.3% in feces). After oral administration of
[14C]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 excreted in the feces increasing with dose. When administered orally,
celecoxib was well distributed to the tissues examined with the highest
concentrations of radioactivity found in the gastrointestinal tract.
Maximal concentration of radioactivity was reached in most all tissues
between 1 and 3 h postdose with the half-life paralleling that of
plasma, with the exception of the gastrointestinal tract tissues.
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