The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the racemate.

Abstract

A single dose of racemic ketorolac (30 mg of the tromethamine salt, Toradol®) was administered by bolus intramuscular injection to four young, healthy volunteers. The concentrations of total (bound plus unbound) (R)-and (S)-ketorolac were measured in plasma for 9 h after dosing. The mean ± s.d. clearance of (S)-ketorolac (45.9 ± 10.1 ml h-1 kg-') exceeded (P = 0.0032) that of the (R)-enantiomer (19.0 ± 5.0 ml h-1 kg-1). The mean ± s.d. AUC ratio for (S)-ketorolac:(R)-ketorolac (0.442 ± 0.043) was signifcantly different from unity (P = 0.0001). The steady-state volume of distribution of (S)-ketorolac (0.135 ± 0.0221 kg-1) was significantly different (P = 0.0013) from that of its optical antipode (0.075 ± 0.014 1 kg-') and the half-lives of (S)-and (R)-ketorolac (2.35 ± 0.23 h and 3.62 ± 0.79 h, respectively) were also significantly different (P = 0.026). These data indicate that the disposition of ketorolac in man is subject to marked enantioselectivity and, because of possible differences in biological activity of (S)-and (R)-ketorolac, emphasize the need to monitor separate stereoisomer concentrations of the drug if pharmacological data are to be interpreted correctly.

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.…”

“…The S(-)-enantiomer of ketorolac has been show to be a significantly more potent analgesic than the R(+)-enantiomer in animal studies [3]. Pharmacokinetics of ketorolac as a total of two enantiomers in humans have been extensively reported [4][5][6][7]. Earlier reports indicate that in humans the plasma concentration vs. time curves of ketorolac enantiomers were superimposable [4].…”

“…Various methods have been described for measurement of ketorolac without differentiating between the enantiomers [8][9][10]. Other methods have recently been reported for the resolution of the ketorolac enantiomers either by first forming diasteromers and separating them on achirial columns [7,11,12,15], or by using chiral columns for separation [2,6,7,13,14]. However, many of the methods employed raise the possibility of ketorolac racemization.…”

“…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].…”

Formation and reactivity of acyl glucuronides: The influence of chirality

“…In addition, when performing enantioselective studies with chiral drugs metabolized to acyl-linked glucuronides, the possibility of base-catalyzed racemization of the aglycone should be addressed as noted when urinary quantification of the acyl glucuronides of (R)-and (S)-ketorolac was attempted. 88 …”