Enantioselective Tissue Distribution of Ketorolac and its Enantiomers in Rats

Abstract

The difference in tissue distribution of Ketorolac and its enantiomers were investigated in wistar rats. Separate high performance liquid chromatographic method was developed and validated for determination of Ketorolac and its enantiomers. Oyster BDS (150×4.6 mm id., 5 μm particle size) column was used for determination of concentration of Ketorolac. Ketorolac enantiomers were determined using Chiral-AGP column (100×4.0 mm I.D., particle size 5 μ, Chrom tech Ltd, Sweden). Detection was done at wavelength of 322 nm using an ultraviolet detector in the analytical system. Ketorolac enantiomers exhibit difference in their disposition in Wistar rats. In kidney, there was a significant difference in pharmacokinetic parameters. The C_max was nearly 4 times and AUC_0–∞ was found to be more than double for S (−) Ketorolac than that of R (+) Ketorolac. MRT, K_e and t_1/2 differ significantly in kidney. In liver, C_max was found to be approximately 69% higher for S (−) Ketorolac compared to R (+) Ketorolac. AUC_0–∞ did not differ significantly for the enantiomers in liver. In liver, S (−) Ketorolac eliminated very fast in comparison to R (+) Ketorolac having t_1/2 (one third) in comparison to R (+) Ketorolac. In lungs, there was no difference observed for C_max and other parameters but AUC_0–∞ was found to be marginally higher for S (−) ketorolac.

Key words

ketorolac - enantiomers - pharmacokinetics - tissue distribution

• References

• 1 Rooks WH, Maloney PJ, Shott LD et al. The analgesic and anti-inflammatory profile of Ketorolac and its tromethamine salt. Drugs Exp Clin Res 1985; 11: 479-492
• 2 Pallapies D, Salinger A, Meyer Zum Gottesberge A et al. Effects of lysine Clonixinate and Ketorolac tromethamine on prostanoid release from various rat organs incubated ex vivo. Life Sci 1995; 57: 83-89
• 3 Zhang Y, Shaffer A, Portanova J et al. Inhibition of cyClooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E₂ production. J Pharmacol Exp Therap 1997; 283: 1069-1075
• 4 Warner TD, Mitchell JA. Cyclo-oxygenases: new forms, new inhibitors and lessons from the Clinic. FASEB J 2004; 18: 790-804
• 5 Galan-Herrera JF, Poo JL, Maya-Barrios JA et al. Bioavailability of two sublingual formulations of Ketorolac tromethamine 30 mg: A randomized, open-label, single-dose, two-period crossover comparison in healthy Mexican adult volunteers. Clin Therap 2008; 30: 1667-1674
• 6 Gillis JC, Brogden RN. Ketorolac: A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997; 53: 139-188
• 7 Guzman A, Yuste F, Toscana RA et al. Absolute configuration of (-)-5-benzoyl-1, 2-dihydro-3 H-pyrrolo [1, 2-alpha] pyrrole-1-carboxylic acid, the active enantiomer of Ketorolac. J Med Chem 1986; 29: 589-591
• 8 Nagilla R, Deshmukh DD, Copedge KJ et al. The pharmacokinetics of Ketorolac enantiomers following intramuscular administration of the racemate. J Vet Pharmacol Ther 2009; 32: 49-55
• 9 Jung D, Mroszczak E, Bynum L. Pharmacokinetics of Ketorolac tromethamine in humans after intravenous, intramuscular and oral administration. Eur J Clin Pharmacol 1988; 35: 423-425
• 10 Mindy N. Cohen, Uwe Christians, Thomas H et al. Pharmacokinetics of Single-Dose Intravenous Ketorolac in Infants Aged 2–11 Months. Anesth Analg 2011; 112: 655-660
• 11 Anne MLynn, Bradford Heidi, Eric DK et al. Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months. Paediatr Anaesth 2011; 21: 325-334
• 12 Kauffman RE, Lieh-Lai MW, Uy HG et al. Enantiomer-selective pharmacokinetics and metabolism of Ketorolac in children. Clin Pharmacol Ther 1999; 65: 382-388
• 13 Hamunen K, Maunuksela EL, Sarvela J et al. Stereoselective pharmacokinetics of Ketorolac in children, adolescents and adults. Acta Anaesthesiol Scand 1999; 43: 1041-1046
• 14 Hayball PJ, Wrobel J, Tamblyn JG et al. The pharmacokinetics of Ketorolac enantiomers following intramuscular administration of the racemate. Br J Clin Pharmac 1994; 37: 75-78
• 15 Drover DR, Hammer GB, Anderson BJ. The pharmacokinetics of Ketorolac after single postoperative intranasal administration in adolescent patients. Anesth Analg 2012; 114: 1270-1276
• 16 Pasloske K, Renaud R, Burger J et al. Pharmacokinetics of Ketorolac after intravenous and oral single dose administration in dogs. J Vet Pharmacol Ther 1999; 22: 314-319
• 17 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
• 18 Nagilla R, Deshmukh DD, Duran SH. Stereoselective pharmacokinetics of Ketorolac in calves after a single intravenous and oral dose. J Vet Pharmacol Ther 2007; 30: 437-442
• 19 Wang M, Liu W, Lu Q. Pharmacokinetic comparison of Ketorolac after intracameral, intravitreal, and suprachoroidal administration in rabbits. Neurosurgery 2012;
• 20 Nagilla R, Deshmukh DD, Copedge KJ et al. Enantiomeric disposition of Ketorolac in goats following administration of a single intravenous and oral dose. J Vet Pharmacol Ther 2009; 32: 49-55
• 21 Santos Y, Ballesteros C, Ros JM et al. Chiral pharmacokinetics of Ketorolac in sheep after intravenous and intramuscular administration of the racemate. J Vet Pharmacol Ther 2001; 24: 443-446