Chiral Kinetics and Dynamics of Ketorolac

Abstract

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

Stereoselective disposition of tiaprofenic acid enantiomers in rats

“…12 However, a net R-to-S bidirectional chiral inversion in vivo and in vitro has been described for oxindanac in dogs, 13 and a net S -to-R bidirectional inversion in vivo and in vitro for ketorolac in rats, mice, and humans. 14 In a recent study of TIA in rats, S -enantiomer plasma concentrations significantly exceeded those of the Renantiomer from 1 hr after subcutaneous administration of R,S -TIA and similar data have been reported in humans. 15 This could be caused by different clearances of the enantiomers and/or by chiral metabolic inversion of TIA enantiomers.…”

A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients

“…This observation is in keeping with reports for improved clinical outcomes associated with ketorolac usage, as compared to other NSAIDs, in breast cancer patients (25–27). Although it has been long recognized that R-enantiomers of NSAIDs are poor inhibitors of cyclooxygenase activity (28–30), potential pharmacologic activities or benefits of the R-enantiomers has remained largely unexplored. Our findings show that Rac1 and Cdc42 are unrealized therapeutic targets in ovarian cancer and use of ketorolac may benefit ovarian cancer patients.…”

Determination of ketorolac enantiomers in plasma using enantioselective liquid chromatography. Application to pharmacokinetic studies

“…The results obtained (Table II) are similar' to those reported by Mroszczak el al., Tsina el al. and Hayball et al [1,2,5,6]. The discrepancies between the previous reported articles is likely to be due to the problem of racemization associated with some of these methods.…”

“…Ketorolac trometamine ( Figure 1) is a potent nonnarcotic analgesic compound with cyclo-oxigenase inhibitory activity that has been developed for oral and parenteral use [1]. It is approved for the treatment of mild tO moderately severe post-operative pain and is marketed as a racemic mixture of R(+)-and S(-)-enantiomers [2].…”

“…Earlier reports indicate that in humans the plasma concentration vs. time curves of ketorolac enantiomers were superimposable [4]. However, some authors have demonstrated recently that each enantiomer can have plasma profiles and therefore pharmacokinetic parameters that differ from those of the other enantiomer and the total drug [1,6,7]. Various methods have been described for measurement of ketorolac without differentiating between the enantiomers [8][9][10].…”