Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat

The marked analgesic efficacy of ketorolac in humans, relative to other non steroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to w hether additional non-NSAID mechanism(s) contribute to its analgesic action s. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmac ological properties in vivo and in vitro using the nonselective cyclooxygen ase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as we ll as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writ hing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema f ormation 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 cor related with their anti-inflammatory potencies, suggesting a common mechani sm. (R,S)-ketorolac was significantly more potent than INDO or DS in vivo. Neither difference in relative potency of COX inhibition for (R,S)-ketorola c over INDO and DS nor activity of (S)-ketorolac at a number of other enzym es, channels, or receptors could account for the differences in observed po tency. The distribution coefficient for (R,S)-ketorolac was approximately 3 0-fold less than for DS or INDO, indicating that (R,S)ketorolac is much les s lipophilic than these NSAIDs. Therefore, the physicochemical and pharmaco kinetics 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.