TY - JOUR T1 - The Absorption, Distribution, Metabolism and Excretion of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Rats and Dogs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1244 LP - 1254 VL - 28 IS - 10 AU - Rita A. Halpin AU - Leslie A. Geer AU - Kanyin E. Zhang AU - Tina M. Marks AU - Dennis C. Dean AU - Allen N. Jones AU - David Melillo AU - George Doss AU - Kamlesh P. Vyas Y1 - 2000/10/01 UR - http://dmd.aspetjournals.org/content/28/10/1244.abstract N2 - Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [14C]rofecoxib precluded accurate determinations of half-life, AUC0–∞(area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [14C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with Cmax occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [14C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-β-d-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3′,4′-dihydrodiol, and 4′-hydroxyrofecoxib sulfate were less abundant, whereascis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-β-d-glucuronide (urine), trans-3,4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile). The American Society for Pharmacology and Experimental Therapeutics ER -