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First published on April 23, 2008, doi:10.1177/0091270008317590

The Journal of Clinical Pharmacology 2008;48:745.

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©© 2008 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology , 10.1177/0091270008317590

Article

PHARMACODYNAMICS Comparative Inhibitory Activity of Etoricoxib, Celecoxib, and Diclofenac on COX-2 Versus COX-1 in Healthy Subjects

Jules I. Schwartz 1*, Aimee L. Dallob 1, Patrick J. Larson 1, Omar F. Laterza 1, Jutta Miller 1, Jane Royalty 2, Karen M. Snyder 1, Derek L. Chappell 1, Deborah A. Hilliard 1, Mary E. Flynn , Paul F. Cavanaugh Jr1, and John A. Wagner 1

1 Merck Research Laboratories
2 Covance GFI Research

* To whom correspondence should be addressed. E-mail: jules_schwartz{at}merck.com.


  Abstract
We determined cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibition in healthy middle-aged subjects (41-65 years) randomly assigned to four 7-day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double-blind, randomized, 4-period crossover study. Maximum inhibition of thromboxane B2 (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E2 in whole blood (cyclo-oxygenase-2 activity) was assessed on day 7 (0-24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B2 versus each comparator (P < .001); placebo 2.4% (95% confidence interval: –8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E2 synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo-oxygenase-1 and cyclo-oxygenase-2, whereas etoricoxib and celecoxib significantly inhibit cyclo-oxygenase-2 and do not substantially inhibit cyclo-oxygenase-1.
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