Abstract
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).
Footnotes
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Send reprint requests to: Kamlesh P. Vyas, Ph.D., Merck Research Laboratories, Merck & Co., Inc., WP75A-203, West Point, PA 19486. E-mail: kamlesh_vyas{at}merck.com
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↵1 Current address: Agouron Pharmaceuticals, Inc., 4215 Sorrento Valley Blvd., San Diego CA, 92121.
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↵4 R. Zamboni, unpublished data, Merck Frosst Canada, Kirkland, Quebec.
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↵5 T. A. Baillie and coworkers, manuscript in preparation, Merck Research Laboratories, West Point, PA.
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↵3 VIOXX is a registered trademark of Merck & Co., Inc.
- Abbreviations used are::
- PG
- prostaglandin
- COX
- cyclooxygenase
- PGHS
- prostaglandin endoperoxide synthase
- TFA
- trifluoroacetic acid
- DMSO
- dimethyl sulfoxide
- Received March 16, 2000.
- Accepted July 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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