RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1244
OP 1254
VO 28
IS 10
A1 Rita A. Halpin
A1 Leslie A. Geer
A1 Kanyin E. Zhang
A1 Tina M. Marks
A1 Dennis C. Dean
A1 Allen N. Jones
A1 David Melillo
A1 George Doss
A1 Kamlesh P. Vyas
YR 2000
UL http://dmd.aspetjournals.org/content/28/10/1244.abstract
AB 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