The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selec tive inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential dec ay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [C-1 4]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to inf inity), and hence, bioavailability. After i.v. administration of [C-14]rofe coxib to dogs, plasma clearance, volume of distribution at steady state, an d elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, a nd 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C-max occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats an d dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) adminis tration, except in rats where no additional increase was observed between t he 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 occ urred primarily by the biliary route in rats and dogs, except after i.v. ad ministration of [C-14]rofecoxib to dogs, where excretion was divided betwee n biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydrox yrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats i n urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-h ydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihy drorofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O -beta-D-glucuronide (urine), trans-3,4- dihydro-rofecoxib (urine), and 5-hy droxyrofecoxib (bile).