Jett M F, Ramesha C S, Brown C D, Chiu S, Emmett C, Voronin T, Sun T, O'Yang C, Hunter J C, Eglen R M, Johnson R M
Center for Biological Research, Roche Bioscience, Palo Alto, California 94304, USA.
J Pharmacol Exp Ther. 1999 Mar;288(3):1288-97.
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.
与其他非甾体抗炎药（NSAIDs）相比，酮咯酸在人体中具有显著的镇痛效果，这引发了人们对于是否存在其他非NSAID机制参与其镇痛作用的猜测。为了评估这种可能性，我们以非选择性环氧化酶（COX）抑制剂[吲哚美辛（INDO）和双氯芬酸钠（DS）]以及选择性COX-2抑制剂塞来昔布作为对照，在体内和体外对（R,S）-酮咯酸的药理特性进行了表征。消旋体（R,S）-酮咯酸在醋酸诱导的扭体试验、角叉菜胶诱导的爪部痛觉过敏试验以及角叉菜胶诱导的大鼠足部水肿形成试验中的效力相似；半数抑制剂量（ID50）值分别为0.24、0.29和0.08mg/kg。（R,S）-酮咯酸的作用具有立体特异性，在上述试验中，（S）-酮咯酸具有消旋体的生物活性。（R,S）-、（S）-和（R）-酮咯酸、INDO以及DS的镇痛效力与其抗炎效力高度相关，提示存在共同机制。（R,S）-酮咯酸在体内的效力显著高于INDO或DS。无论是（R,S）-酮咯酸相对于INDO和DS在COX抑制相对效力上的差异，还是（S）-酮咯酸在许多其他酶、通道或受体上的活性，都无法解释所观察到的效力差异。（R,S）-酮咯酸的分配系数比DS或INDO约低30倍，表明（R,S）-酮咯酸的亲脂性远低于这些NSAIDs。因此，（R,S）-酮咯酸的物理化学和药代动力学特性可能优化了（S）-酮咯酸在其生物靶点的浓度，从而在体内产生更高的疗效和效力。
