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

Livia Capponi Division of Veterinary Pharmacology and Toxicology, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.

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Andrea Schmitz Division of Veterinary Pharmacology and Toxicology, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.

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Wolfgang Thormann Department of Clinical Pharmacology, Faculty of Medicine, University of Bern, 3010 Bern, Switzerland.

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Regula Theurillat Department of Clinical Pharmacology, Faculty of Medicine, University of Bern, 3010 Bern, Switzerland.

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Meike Mevissen Division of Veterinary Pharmacology and Toxicology, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.

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Abstract

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.

Abstract

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.

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