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Journal of veterinary pharmacology and therapeutics2008; 31(5); 446-455; doi: 10.1111/j.1365-2885.2008.00972.x

Stereoselective biotransformation of ketamine in equine liver and lung microsomes.

Abstract: Stereoselectivity has to be considered for pharmacodynamic and pharmacokinetic features of ketamine. Stereoselective biotransformation of ketamine was investigated in equine microsomes in vitro. Concentration curves were constructed over time, and enzyme activity was determined for different substrate concentrations using equine liver and lung microsomes. The concentrations of R/S-ketamine and R/S-norketamine were determined by enantioselective capillary electrophoresis. A two-phase model based on Hill kinetics was used to analyze the biotransformation of R/S-ketamine into R/S-norketamine and, in a second step, into R/S-downstream metabolites. In liver and lung microsomes, levels of R-ketamine exceeded those of S-ketamine at all time points and S-norketamine exceeded R-norketamine at time points below the maximum concentration. In liver and lung microsomes, significant differences in the enzyme velocity (V(max)) were observed between S- and R-norketamine formation and between V(max) of S-norketamine formation when S-ketamine was compared to S-ketamine of the racemate. Our investigations in microsomal reactions in vitro suggest that stereoselective ketamine biotransformation in horses occurs in the liver and the lung with a slower elimination of S-ketamine in the presence of R-ketamine. Scaling of the in vitro parameters to liver and lung organ clearances provided an excellent fit with previously published in vivo data and confirmed a lung first-pass effect.
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Publication Date: 2008-11-13 PubMed ID: 19000264PubMed Central: PMC2821671DOI: 10.1111/j.1365-2885.2008.00972.xGoogle Scholar: Lookup
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  • Journal Article
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  • Intramural
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigated the varying rates at which a drug called ketamine is metabolically processed in horse liver and lung cells. The researchers found that the rate differed based on the structural variant of the drug and the organ in which it was processed, revealing new insights into how ketamine behaves in the body of horses.

Study context

  • Ketamine is a medication with multiple uses such as in anesthesia and pain management. It exists in two structural forms, referred to as R and S stereoisomers.
  • These stereoisomers can sometimes be metabolized differently in the body, due to their distinct 3D structures- a phenomenon known as stereoselective biotransformation.
  • This research aimed to investigate the stereoselective biotransformation of ketamine in horse liver and lung cells, as previous research has suggested that varying rates of metabolism could occur in different organs.

Methodology

  • The researchers conducted the study in vitro, meaning they performed the experiments using cells in a controlled environment outside of a living organism.
  • They used horse liver and lung cells, also known as microsomes, to test how they metabolized R and S ketamine.
  • The concentrations of the stereoisomers and their metabolites were measured over time using a method called enantioselective capillary electrophoresis.
  • The researchers used a two-phase model based on Hill kinetics to analyze the data.

Findings

  • The researchers found that both in liver and lung cells, the concentration of R-ketamine was higher than that of S-ketamine at all tested time points. Conversely, the concentration of S-norketamine, a metabolite of ketamine, was higher than that of R-norketamine at times below the maximum concentration.
  • The metabolism rate, or enzyme velocity, differed significantly between the formation of S- and R-norketamine and between the maximum enzyme velocities when comparing S-ketamine with the racemic mix of both forms.
  • This shows that stereo-selective biotransformation of ketamine indeed occurs in horses and it is more pronounced in the liver and the lung.

Significance of the study

  • This research provides important information on how ketamine is processed in the body of horses, which can guide dosing and administration decisions in veterinary medicine.
  • The findings confirm that the lungs carry out a ‘first-pass effect’, metabolizing a substantial amount of the drug before it reaches systemic circulation.
  • The study also shows how in vitro experiments can be successfully correlated with in vivo conditions, providing further confidence in the use of in vitro studies.

Cite This Article

APA
Schmitz A, Portier CJ, Thormann W, Theurillat R, Mevissen M. (2008). Stereoselective biotransformation of ketamine in equine liver and lung microsomes. J Vet Pharmacol Ther, 31(5), 446-455. https://doi.org/10.1111/j.1365-2885.2008.00972.x

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 31
Issue: 5
Pages: 446-455

Researcher Affiliations

Schmitz, A
  • Division of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Portier, C J
    Thormann, W
      Theurillat, R
        Mevissen, M

          MeSH Terms

          • Analgesics / metabolism
          • Analgesics / pharmacokinetics
          • Animals
          • Biotransformation
          • Female
          • Horses
          • In Vitro Techniques
          • Ketamine / analogs & derivatives
          • Ketamine / metabolism
          • Ketamine / pharmacokinetics
          • Lung / metabolism
          • Male
          • Metabolic Clearance Rate
          • Microsomes, Liver / metabolism
          • Models, Biological
          • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
          • Stereoisomerism
          • Substrate Specificity

          Grant Funding

          • Z01 ES048002-21 / Intramural NIH HHS

          References

          This article includes 35 references
          1. Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain.. Br J Anaesth 1996 Nov;77(5):625-31.
            pubmed: 8957979doi: 10.1093/bja/77.5.625google scholar: lookup
          2. Delatour P, Jaussaud P, Courtot D, Fau D. Enantioselective N-demethylation of ketamine in the horse.. J Vet Pharmacol Ther 1991 Jun;14(2):209-12.
            pubmed: 1920610doi: 10.1111/j.1365-2885.1991.tb00825.xgoogle scholar: lookup
          3. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.. Annu Rev Pharmacol Toxicol 2003;43:149-73.
            pubmed: 12171978doi: 10.1146/annurev.pharmtox.43.100901.140251google scholar: lookup
          4. Dyke TM, Hubbell JA, Sams RA, Hinchcliff KW. Hepatic blood flow in horses during the recuperative period from maximal exercise.. Am J Vet Res 1998 Nov;59(11):1476-80.
            pubmed: 9829410
          5. Eichenberger U. Evaluation der Aufwachphase von Katzen nach einer routinemässigen Ovariektomie:Vergleich S(+) – Ketamin versus Ketaminrazemat. Vetsuisse-Fakultät der Universität Bern; Vetsuisse 2005. pp. 1–58.
          6. Fielding CL, Brumbaugh GW, Matthews NS, Peck KE, Roussel AJ. Pharmacokinetics and clinical effects of a subanesthetic continuous rate infusion of ketamine in awake horses.. Am J Vet Res 2006 Sep;67(9):1484-90.
            pubmed: 16948590doi: 10.2460/ajvr.67.9.1484google scholar: lookup
          7. Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD, Brune K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method.. Br J Anaesth 1993 Jun;70(6):666-71.
            pubmed: 8329260doi: 10.1093/bja/70.6.666google scholar: lookup
          8. Henthorn TK, Krejcie TC, Niemann CU, Enders-Klein C, Shanks CA, Avram MJ. Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective.. Anesthesiology 1999 Dec;91(6):1733-43.
            pubmed: 10598617doi: 10.1097/00000542-199912000-00027google scholar: lookup
          9. Hijazi Y, Boulieu R. Protein binding of ketamine and its active metabolites to human serum.. Eur J Clin Pharmacol 2002 Apr;58(1):37-40.
            pubmed: 11956671doi: 10.1007/s00228-002-0439-4google scholar: lookup
          10. Hijazi Y, Bodonian C, Bolon M, Salord F, Boulieu R. Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury.. Br J Anaesth 2003 Feb;90(2):155-60.
            pubmed: 12538370doi: 10.1093/bja/aeg028google scholar: lookup
          11. Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons.. Anesth Analg 1996 Sep;83(3):505-12.
            pubmed: 8780271doi: 10.1097/00000539-199609000-00011google scholar: lookup
          12. Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance.. Biochem Pharmacol 1994 Apr 29;47(9):1469-79.
            pubmed: 8185657doi: 10.1016/0006-2952(94)90520-7google scholar: lookup
          13. Ihmsen H, Geisslinger G, Schüttler J. Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine.. Clin Pharmacol Ther 2001 Nov;70(5):431-8.
            pubmed: 11719729doi: 10.1067/mcp.2001.119722google scholar: lookup
          14. Kaka JS, Klavano PA, Hayton WL. Pharmacokinetics of ketamine in the horse.. Am J Vet Res 1979 Jul;40(7):978-81.
            pubmed: 507501
          15. Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes.. Anesthesiology 1992 Dec;77(6):1201-7.
            pubmed: 1466470doi: 10.1097/00000542-199212000-00022google scholar: lookup
          16. Klepstad P, Maurset A, Moberg ER, Oye I. Evidence of a role for NMDA receptors in pain perception.. Eur J Pharmacol 1990 Oct 23;187(3):513-8.
            pubmed: 1963598doi: 10.1016/0014-2999(90)90379-kgoogle scholar: lookup
          17. Knobloch M, Portier CJ, Levionnois OL, Theurillat R, Thormann W, Spadavecchia C, Mevissen M. Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion.. Toxicol Appl Pharmacol 2006 Nov 1;216(3):373-86.
            pmc: PMC2039908pubmed: 16919695doi: 10.1016/j.taap.2006.06.011google scholar: lookup
          18. Koo JW, Parham F, Kohn MC, Masten SA, Brock JW, Needham LL, Portier CJ. The association between biomarker-based exposure estimates for phthalates and demographic factors in a human reference population.. Environ Health Perspect 2002 Apr;110(4):405-10.
            pmc: PMC1240804pubmed: 11940459doi: 10.1289/ehp.02110405google scholar: lookup
          19. Lakritz J, Winder BS, Noorouz-Zadeh J, Huang TL, Buckpitt AR, Hammock BD, Plopper CG. Hepatic and pulmonary enzyme activities in horses.. Am J Vet Res 2000 Feb;61(2):152-7.
            pubmed: 10685686doi: 10.2460/ajvr.2000.61.152google scholar: lookup
          20. Larenza MP, Knobloch M, Landoni MF, Levionnois OL, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration in Shetland ponies sedated with xylazine.. Vet J 2008 Sep;177(3):432-5.
            doi: 10.1016/j.tvjl.2007.05.005pubmed: 17604192google scholar: lookup
          21. Larenza MP, Landoni MF, Levionnois OL, Knobloch M, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies.. Br J Anaesth 2007 Feb;98(2):204-12.
            pubmed: 17218377doi: 10.1093/bja/ael336google scholar: lookup
          22. Mackinnon M, Sutherland E, Simon FR. Effects of ethinyl estradiol on hepatic microsomal proteins and the turnover of cytochrome P-450.. J Lab Clin Med 1977 Dec;90(6):1096-106.
            pubmed: 925482
          23. McConaghy FF, Hodgson DR, Rose RJ, Hales JR. Redistribution of cardiac output in response to heat exposure in the pony.. Equine Vet J Suppl 1996 Jul;(22):42-6.
            pubmed: 8894549doi: 10.1111/j.2042-3306.1996.tb05030.xgoogle scholar: lookup
          24. OMURA T, SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. II. SOLUBILIZATION, PURIFICATION, AND PROPERTIES.. J Biol Chem 1964 Jul;239:2379-85.
            pubmed: 14209972
          25. Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors.. J Pharmacol Exp Ther 1992 Mar;260(3):1209-13.
            pubmed: 1312163
          26. Persson J, Hasselström J, Maurset A, Oye I, Svensson JO, Almqvist O, Scheinin H, Gustafsson LL, Almqvist O. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity.. Eur J Clin Pharmacol 2002 Feb;57(12):869-75.
            pubmed: 11936706doi: 10.1007/s002280100353google scholar: lookup
          27. Schwieger IM, Szlam F, Hug CC Jr. The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane.. J Pharmacokinet Biopharm 1991 Apr;19(2):145-56.
            pubmed: 2013837doi: 10.1007/bf01073866google scholar: lookup
          28. Theurillat R, Knobloch M, Levionnois O, Larenza P, Mevissen M, Thormann W. Characterization of the stereoselective biotransformation of ketamine to norketamine via determination of their enantiomers in equine plasma by capillary electrophoresis.. Electrophoresis 2005 Oct;26(20):3942-51.
            pubmed: 16167314doi: 10.1002/elps.200500059google scholar: lookup
          29. Theurillat R, Knobloch M, Schmitz A, Lassahn PG, Mevissen M, Thormann W. Enantioselective analysis of ketamine and its metabolites in equine plasma and urine by CE with multiple isomer sulfated beta-CD.. Electrophoresis 2007 Aug;28(15):2748-57.
            pubmed: 17600844doi: 10.1002/elps.200600820google scholar: lookup
          30. Walsh G. Methods of Optimization. Wiley Press New York: 1975. pp. 155–161.
          31. Waterman AE. Influence of premedication with xylazine on the distribution and metabolism of intramuscularly administered ketamine in cats.. Res Vet Sci 1983 Nov;35(3):285-90.
            pubmed: 6665311
          32. Waterman AE, Robertson SA, Lane JG. Pharmacokinetics of intravenously administered ketamine in the horse.. Res Vet Sci 1987 Mar;42(2):162-6.
            pubmed: 3589163
          33. White PF, Marietta MP, Pudwill CR, Way WL, Trevor AJ. Effects of halothane anesthesia on the biodisposition of ketamine in rats.. J Pharmacol Exp Ther 1976 Mar;196(3):545-55.
            pubmed: 1263110
          34. White PF, Way WL, Trevor AJ. Ketamine--its pharmacology and therapeutic uses.. Anesthesiology 1982 Feb;56(2):119-36.
            pubmed: 6892475doi: 10.1097/00000542-198202000-00007google scholar: lookup
          35. White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ. Comparative pharmacology of the ketamine isomers. Studies in volunteers.. Br J Anaesth 1985 Feb;57(2):197-203.
            pubmed: 3970799doi: 10.1093/bja/57.2.197google scholar: lookup

          Citations

          This article has been cited 1 times.
          1. Pargätzi G, Bergadano A, Spadavecchia C, Theurillat R, Thormann W, Levionnois OL. Stereoselective Pharmacokinetics of Ketamine Administered at a Low Dose in Awake Dogs. Animals (Basel) 2024 Mar 27;14(7).
            doi: 10.3390/ani14071012pubmed: 38612251google scholar: lookup
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