PT - JOURNAL ARTICLE AU - Josh J. Yuan AU - Dai-chang Yang AU - Ji Y. Zhang AU - Roy Bible, Jr. AU - Aziz Karim AU - John W. A. Findlay TI - Disposition of a Specific Cyclooxygenase-2 Inhibitor, Valdecoxib, in Human AID - 10.1124/dmd.30.9.1013 DP - 2002 Sep 01 TA - Drug Metabolism and Disposition PG - 1013--1021 VI - 30 IP - 9 4099 - http://dmd.aspetjournals.org/content/30/9/1013.short 4100 - http://dmd.aspetjournals.org/content/30/9/1013.full SO - Drug Metab Dispos2002 Sep 01; 30 AB - Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain. Eight male human subjects each received a single 50-mg oral dose of [14C]valdecoxib. Urine, feces, and blood samples were collected after administration of the radioactive dose. Most of the radioactivity in plasma was associated with valdecoxib and the hydroxylated metabolite of valdecoxib (M1). The estimated terminal half-life for valdecoxib was about 7 h. About 76.1% of the radioactive dose was recovered in urine and 18% of the radioactive dose was recovered in feces. Valdecoxib was extensively metabolized in human, and nine phase I metabolites were identified. The primary oxidative metabolic pathways of valdecoxib involved hydroxylation at either the methyl group to form M1 or N-hydroxylation at the sulfonamide moiety to form M2. Further oxidation of M1 led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide function group in M2 led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The O-glucuronide conjugate of M1 andN-glucuronide conjugate of valdecoxib were the major urinary metabolites, which accounted for 23.3 and 19.5% of the total administered dose, respectively. The remaining urinary metabolites were glucuronide conjugates of other phase I metabolites. Only 3% of the administered dose was recovered in urine as unchanged parent, suggesting that renal clearance is insignificant for valdecoxib. Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <1% of the administered dose. The American Society for Pharmacology and Experimental Therapeutics