Clinical Trials and Therapeutics
Clinical Pharmacology & Therapeutics (1999) 65, 336–347; doi:
Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model*
Elliot W. Ehrich MD1, Aimee Dallob MS1, Inge De Lepeleire MS1, Anne Van Hecken PhD1, Denis Riendeau PhD1, Weiying Yuan PhD1, Arturo Porras PhD1, Johanna Wittreich BS1, James R. Seibold MD1, Paul De Schepper MD, PhD1, Donald R. Mehlisch MD, DDS1 and Barry J. Gertz MD, PhD1
1Departments of Clinical Research, Clinical Pharmacology, Biostatistics, and Drug Metabolism, Merck Research Laboratories, Rahway, NJ; the Department of Clinical Pharmacology, University of Leuven, Leuven, Belgium; the Merck Frosst Centre for Therapeutic Research, Kirkland, Quebac, Canada; the Clinical Research Center, Robert Wood Johnson Medical School, New Brunswick, NJ; and SciRex Corp, Austin, Texas.
Correspondence: Elliot W. Ehrich, MD, Merck & Co, Inc, PO Box 2000, RY32-629, Rahway, NJ 07065. E-mail: elliot_ehrich@merck.com
*Supported by a grant from Merck & Co, Inc.
Received 17 June 1998; Accepted 21 October 1998.
Abstract
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs.
Methods: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain.
Results: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 
mol/L) and indomethacin (IC50, 0.33 mol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 mol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001)
Conclusions: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.
