In vitro evaluation of differences in phase 1 metabolism of ketamine and other analgesics among humans, horses, and dogs

Capponi, Livia; Schmitz, Andrea; Thormann, Wolfgang; Theurillat, Regula; Mevissen, Meike (2009). In vitro evaluation of differences in phase 1 metabolism of ketamine and other analgesics among humans, horses, and dogs. American journal of veterinary research, 70(6), pp. 777-86. Chicago, Ill.: American Veterinary Medical Association 10.2460/ajvr.70.6.777

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OBJECTIVE: To investigate cytochrome P450 (CYP) enzymes involved in metabolism of racemic and S-ketamine in various species and to evaluate metabolic interactions of other analgesics with ketamine. SAMPLE POPULATION: Human, equine, and canine liver microsomes. PROCEDURES: An analgesic was concurrently incubated with luminogenic substrates specific for CYP 3A4 or CYP 2C9 and liver microsomes. The luminescence signal was detected and compared with the signal for negative control samples. Ketamine and norketamine enantiomers were determined by use of capillary electrophoresis. RESULTS: A concentration-dependent decrease in luminescence signal was detected for ibuprofen and diclofenac in the assay for CYP 2C9 in human and equine liver microsomes but not in the assay for CYP 3A4 and methadone or xylazine in any of the species. Coincubation of methadone or xylazine with ketamine resulted in a decrease in norketamine formation in equine and canine liver microsomes but not in human liver microsomes. In all species, norketamine formation was not affected by ibuprofen, but diclofenac reduced norketamine formation in human liver microsomes. A higher rate of metabolism was detected for S-ketamine in equine liver microsomes, compared with the rate for the S-enantiomer in the racemic mixture when incubated with any of the analgesics investigated. CONCLUSIONS AND CLINICAL RELEVANCE: Enzymes of the CYP 3A4 family and orthologs of CYP 2C9 were involved in ketamine metabolism in horses, dogs, and humans. Methadone and xylazine inhibited in vitro metabolism of ketamine. Therefore, higher concentrations and diminished clearance of ketamine may cause adverse effects when administered concurrently with other analgesics.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued] 05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Pharmacology and Toxicology
UniBE Contributor:	Schmitz, Andrea, Thormann, Wolfgang, Theurillat, Regula, Mevissen, Meike
ISSN:	0002-9645
Publisher:	American Veterinary Medical Association
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:07
Last Modified:	05 Dec 2022 14:20
Publisher DOI:	10.2460/ajvr.70.6.777
PubMed ID:	19496669
Web of Science ID:	000266461800013
URI:	https://boris.unibe.ch/id/eprint/29581 (FactScience: 146694)