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Vol. 288, Issue 3, 1288-1297, March 1999

Characterization of the Analgesic and Anti-Inflammatory Activities of Ketorolac and Its Enantiomers in the Rat

Mary-Frances Jett, Chakk S. Ramesha, Carl D. Brown, Sophie Chiu, Caroline Emmett, Tatyana Voronin, Thomas Sun, Counde O'Yang, John C. Hunter, Richard M. Eglen and Randolph M. Johnson

Center for Biological Research (M.-F.J., C.E., J.C.H., R.M.E., R.M.J.), Preclinical Research and Development (C.D.B., T.S.), Medicinal Chemistry (C.O.), Radiochemistry Group (T.V.), and Central R & D (S.C.) in the Neurobiology Unit or Inflammatory Disease Unit (C.S.R.) of Roche Bioscience, Palo Alto, California

The marked analgesic efficacy of ketorolac in humans, relative to other nonsteroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to whether additional non-NSAID mechanism(s) contribute to its analgesic actions. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmacological properties in vivo and in vitro using the nonselective cyclooxygenase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as well as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writhing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema formation in rats; ID50 values = 0.24, 0.29, and 0.08 mg/kg, respectively. (R,S)-ketorolac's actions were stereospecific, with (S)-ketorolac possessing the biological activity of the racemate in the above tests. The analgesic potencies for (R,S)-, (S)-, and (R)-ketorolac, INDO, and DS were highly correlated with their anti-inflammatory potencies, suggesting a common mechanism. (R,S)-ketorolac was significantly more potent than INDO or DS in vivo. Neither difference in relative potency of COX inhibition for (R,S)-ketorolac over INDO and DS nor activity of (S)-ketorolac at a number of other enzymes, channels, or receptors could account for the differences in observed potency. The distribution coefficient for (R,S)-ketorolac was approximately 30-fold less than for DS or INDO, indicating that (R,S)-ketorolac is much less lipophilic than these NSAIDs. Therefore, the physicochemical and pharmacokinetics properties of (R,S)-ketorolac may optimize the concentrations of (S)-ketorolac at its biological target(s), resulting in greater efficacy and potency in vivo.

0022-3565/99/2883-1288$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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