Stereoselective Tissue Distribution of Ketolorac in Rats – Differential Uptake of Ketolorac Enantiomers in Certain Tissues

Dubey et al. (2015) have described the enantioselective tissue distribution of ketolorac in the rats [1]. Although the distribution of the enantiomers of ketolorac and racemate was evaluated in 4 important tissues, namely: heart, lungs, liver and kidney, the key generic message that stereoselective plasma pharmacokinetics may not be reflected in all the tissues are effectively conveyed [1]. The intent of this note is to further critically evaluate the published data and provide additional perspectives.

Despite the well-planned experimental design that involved time dependent pharmacokinetic sampling from the various tissues, the authors have failed to report the stereoselective pharmacokinetics of ketolorac derived from plasma in this study [1]. Such data would have enabled comparing and contrasting the tissue levels with those observed in the plasma for both ketolorac enantiomers. Also, the inclusion of plasma data would have been important because there is a general notion that blood is in sync with the tissues and therefore the observed stereoselectivity for ketolorac in the blood (plasma) would likely be reflected in the tissues. Previously, Jamali et al. (1990) and Dubey et al. (2013) haver reported the stereoselective pharmacokinetics of ketolorac in rats; while Jamali et al. (1990) had an interesting study design that included the oral administrations of the racemate, S-ketolorac and R-ketolorac, the work of Dubey et al. (2013) examined the stereoselective pharmacokinetics after intravenous dosing of ketolorac racemate. In the investigation of Jamali et al. (1990), the plasma pharmacokinetics of ketolorac exhibited significant stereoselectivity following the racemate administration such that the levels of the R-ketolorac was found to be consistently higher at various time points as compared to S-ketolorac and a mean area under the plasma concentration vs. time curve (AUC) ratio of S-ketolorac/R-ketolorac was reported to be 0.45 in the rats [2]. Interestingly, the administration of the pure S-ketolorac resulted in the plasma bioavailability of the R-ketolorac (almost 6.7% of the total AUC) suggesting that there was an inversion of S-ketolorac to R-ketolorac perhaps mediated by the small intestine or the liver as a result of the first pass effect [2]. However, such a chiral inversion was non-existent when the pure R-ketolorac was administered to rats [2]. The investigation of Dubey et al. (2013) showed that stereoselectivity of ketolorac was not entirely dependent on the presystemic metabolism although the propensity in the observed stereoselectivity appeared to be different after intravenous as compared to that of the oral administration [2] [3]. In view of the earlier reported stereoselective pharmacokinetics of ketolorac and the possibility for chiral inversion in certain tissues, the recent work of Dubey et al. (2015) assumes high importance [1].

Hitherto a detailed tissue distribution study of ketolorac enantiomers in the rats examining the pharmacokinetics has not been reported in the literature. Using the stereoselective plasma pharmacokinetic data from the earlier work for ketolorac enantiomers [2], if one examines the tissue pharmacokinetics of ketolorac enantiomers the following deductions can be arrived at: a) heart, lung and liver tissue pharmacokinetic data showed no stereoselectivity in the pharmacokinetics of ketolorac enantiomers [1] suggesting that the uptake to these tissues presumably by uptake transporters may favour S-ketolorac over the R-enantiomer; b) kidney tissue pharmacokinetic data of both ketolorac enantiomers [1] appeared to be consistent with the plasma pharmacokinetic data with respect to stereoselectivity [2]. Since the elimination of ketolorac is governed by both renal and non-renal mechanisms in the rat [4], the observed stereoselectivity in the plasma may be partly explained by the faster renal excretion of the S-ketolorac as compared to that of the R-enantiomer.

A recently published tissue and plasma pharmacokinetic data of the enantiomers of naftopidil highlights the importance of simultaneous measurements of the plasma and tissue levels [5]. The bioavailability of naftopidil after intra-gastric administration in rats favored the (S)-(-)-enantiomer of naftopidil which showed a 2-fold higher bioavailability as compared to the (R)-(+)-enantiomer [5]. However, examination of the tissue distribution and pharmacokinetics for the 2 enantiomers of naftopidil revealed a contrasting picture to that seen in plasma; in all 3 tissues examined, namely: the prostrate, liver and kidney, the bioavailability of the (R)-(+)-naftopidil was greater than that of the (S)-(-)-enantiomer and the corresponding (R)-(+)/(S)-(-) ratios were 3.16, 1.33 and 2.90, respectively, in the 3 tissues [5].

In summary the interesting published data of tissue pharmacokinetics of ketolorac enantiomers when put in context to the earlier reported stereoselective pharmacokinetic data of ketolorac demonstrated the local uptake of ketolorac enantiomers into various tissues may be under the influence of uptake transporters present in the tissues and therefore it is erroneous to assume that the stereoselectivity observed in the plasma will remain the same in the tissues for the racemic drugs. Another area that may be of significant interest would be to evaluate the time dependent biliary excretion of ketolorac enantiomers in the rat since non-renal mechanisms may also be equally important for the elimination of ketolorac. Such data would enable to determine the role of renal vs. biliary excretion to contribute for the observed stereoselectivity of ketolorac.

• References

• 1 Dubey SK, Anand A, Saha RN. Enantioselective Tissue Distribution of Ketorolac and its Enantiomers in Rats. Drug Res (Stuttg) 2015; 65: 428-4331
• 2 Jamali F, Lovlin R, Corrigan BW et al. Stereospecific pharmacokinetics and toxicodynamics of Ketorolac after oral administration of the racemate and optically pure enantiomers to the rat. Chirality 1999; 11: 201-205
• 3 Dubey SK, Saha RN, Mittapelly N et al. Enantioselective disposition after single dose I.V administration of ketorolac in male Wistar rats. Drug Res (Stuttg) 2013; 63: 34-37
• 4 Mroszczak EJ, Lee FW, Combs D et al. Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos 1987; 15: 618-626
• 5 Liu X, Zhang X, Huang J et al. Enantiospecific determination of naftopidil by RRLC-MS/MS reveals stereoselective pharmacokinetics and tissue distributions in rats. Pharm Biomed Anal 2015; 112: 147-154