Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans

Eur J Clin Pharmacol. 2000 May;56(2):167-74. doi: 10.1007/s002280050736.


Objective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor.

Methods: Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose.

Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient.

Conclusion: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone / biosynthesis
  • Double-Blind Method
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / toxicity
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / drug effects
  • Lactones / administration & dosage
  • Lactones / pharmacokinetics*
  • Lactones / toxicity*
  • Male
  • Membrane Proteins
  • Metabolic Clearance Rate
  • Placebos
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Sulfones
  • Thromboxane B2 / blood


  • Enzyme Inhibitors
  • Isoenzymes
  • Lactones
  • Membrane Proteins
  • Placebos
  • Sulfones
  • rofecoxib
  • Thromboxane B2
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone