Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans.
Abstract: To identify and characterize cytochrome P450 enzymes (CYPs) responsible for the metabolism of racemic ketamine in 3 mammalian species in vitro by use of chemical inhibitors and antibodies. Methods: Human, canine, and equine liver microsomes and human single CYP3A4 and CYP2C9 and their canine orthologs. Methods: Chemical inhibitors selective for human CYP enzymes and anti-CYP antibodies were incubated with racemic ketamine and liver microsomes or specific CYPs. Ketamine N-demethylation to norketamine was determined via enantioselective capillary electrophoresis. Results: The general CYP inhibitor 1-aminobenzotriazole almost completely blocked ketamine metabolism in human and canine liver microsomes but not in equine microsomes. Chemical inhibition of norketamine formation was dependent on inhibitor concentration in most circumstances. For all 3 species, inhibitors of CYP3A4, CYP2A6, CYP2C19, CYP2B6, and CYP2C9 diminished N-demethylation of ketamine. Anti-CYP3A4, anti-CYP2C9, and anti-CYP2B6 antibodies also inhibited ketamine N-demethylation. Chemical inhibition was strongest with inhibitors of CYP2A6 and CYP2C19 in canine and equine microsomes and with the CYP3A4 inhibitor in human microsomes. No significant contribution of CYP2D6 to ketamine biotransformation was observed. Although the human CYP2C9 inhibitor blocked ketamine N-demethylation completely in the canine ortholog CYP2C21, a strong inhibition was also obtained by the chemical inhibitors of CYP2C19 and CYP2B6. Ketamine N-demethylation was stereoselective in single human CYP3A4 and canine CYP2C21 enzymes. Conclusions: Human-specific inhibitors of CYP2A6, CYP2C19, CYP3A4, CYP2B6, and CYP2C9 diminished ketamine N-demethylation in dogs and horses. To address drug-drug interactions in these animal species, investigations with single CYPs are needed.
Publication Date: 2011-10-26 PubMed ID: 22023129DOI: 10.2460/ajvr.72.11.1505Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates and characterizes the role of cytochrome P450 enzymes in the metabolism of ketamine in humans, dogs, and horses. The study used chemical inhibitors and anti-CYP antibodies to examine the inhibition of ketamine N-demethylation in these species.
Methods
- Human, canine, and equine liver microsomes were used, along with specific human CYP3A4 and CYP2C9 enzymes and their canine versions.
- Chemical inhibitors selective for human CYP enzymes and anti-CYP antibodies were used to examine the interaction with ketamine metabolism.
- Ketamine N-demethylation to norketamine was determined via enantioselective capillary electrophoresis.
Results
- The general CYP inhibitor 1-aminobenzotriazole nearly fully blocked ketamine metabolism in human and canine liver microsomes, but not in equine versions.
- Inhibition of norketamine formation was fundamentally dependent on inhibitor concentration.
- In all three species, the inhibitors of CYP3A4, CYP2A6, CYP2C19, CYP2B6, and CYP2C9 reduced ketamine N-demethylation.
- Anti-CYP3A4, anti-CYP2C9, and anti-CYP2B6 antibodies also inhibited N-demethylation of ketamine, implying the vital role of these CYPs in ketamine metabolism.
- CYP2A6 and CYP2C19 inhibitors caused the most significant inhibition in canine and equine microsomes, while the CYP3A4 inhibitor was the most effective in human microsomes.
- CYP2D6 had no significant impact on ketamine biotransformation in any species.
- The human CYP2C9 inhibitor completely blocked ketamine N-demethylation in the canine version CYP2C21, indicating the functional overlap between these enzymes.
- In human CYP3A4 and canine CYP2C21 enzymes, ketamine N-demethylation exhibited stereoselectivity.
Conclusions
- Human-specific inhibitors of CYP2A6, CYP2C19, CYP3A4, CYP2B6, and CYP2C9 reduced ketamine N-demethylation in dogs and horses, demonstrating a cross-species effect.
- The results suggest that further investigations with single CYPs are necessary to understand drug-drug interactions in these animal species.
Cite This Article
APA
Mössner LD, Schmitz A, Theurillat R, Thormann W, Mevissen M.
(2011).
Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans.
Am J Vet Res, 72(11), 1505-1513.
https://doi.org/10.2460/ajvr.72.11.1505 Publication
Researcher Affiliations
- Division of Veterinary Pharmacology & Toxicology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
MeSH Terms
- Analgesics / chemistry
- Analgesics / metabolism
- Anesthetics, Dissociative / chemistry
- Anesthetics, Dissociative / metabolism
- Animals
- Antibodies, Blocking / chemistry
- Antibodies, Blocking / pharmacology
- Biotransformation
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System / metabolism
- Dogs
- Electrophoresis, Capillary
- Enzyme Inhibitors / metabolism
- Enzyme Inhibitors / pharmacology
- Female
- Horses
- Humans
- Ketamine / analogs & derivatives
- Ketamine / chemistry
- Ketamine / metabolism
- Male
- Methylation
- Microsomes, Liver / drug effects
- Microsomes, Liver / enzymology
- Microsomes, Liver / metabolism
- Species Specificity
- Stereoisomerism
Citations
This article has been cited 9 times.- Zanza C, Piccolella F, Racca F, Romenskaya T, Longhitano Y, Franceschi F, Savioli G, Bertozzi G, De Simone S, Cipolloni L, La Russa R. Ketamine in Acute Brain Injury: Current Opinion Following Cerebral Circulation and Electrical Activity. Healthcare (Basel) 2022 Mar 17;10(3).
- Bahr R, Lopez A, Rey JA. Intranasal Esketamine (Spravato(TM)) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant. P T 2019 Jun;44(6):340-375.
- de Montellano PRO. 1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology. Med Chem (Los Angeles) 2018;8(3).
- Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EFR, Albuquerque EX, Thomas CJ, Zarate CA Jr, Gould TD. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev 2018 Jul;70(3):621-660.
- Tillmann S, Pereira VS, Liebenberg N, Christensen AK, Wegener G. ZL006, a small molecule inhibitor of PSD-95/nNOS interaction, does not induce antidepressant-like effects in two genetically predisposed rat models of depression and control animals. PLoS One 2017;12(8):e0182698.
- Giroux MC, Santamaria R, Hélie P, Burns P, Beaudry F, Vachon P. Physiological, pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia. Exp Anim 2016;65(1):63-75.
- Mazzeffi M, Johnson K, Paciullo C. Ketamine in adult cardiac surgery and the cardiac surgery Intensive Care Unit: an evidence-based clinical review. Ann Card Anaesth 2015 Apr-Jun;18(2):202-9.
- Giroux MC, Hélie P, Burns P, Vachon P. Anesthetic and pathological changes following high doses of ketamine and xylazine in Sprague Dawley rats. Exp Anim 2015;64(3):253-60.
- Veilleux-Lemieux D, Castel A, Carrier D, Beaudry F, Vachon P. Pharmacokinetics of ketamine and xylazine in young and old Sprague-Dawley rats. J Am Assoc Lab Anim Sci 2013 Sep;52(5):567-70.
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