Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro

Portmann, Simone; Kwan, Hiu Ying; Theurillat, Regula; Schmitz, Andrea; Mevissen, Meike; Thormann, Wolfgang (2010). Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro. Journal of chromatography A, 1217(51), pp. 7942-8. Amsterdam: Elsevier Science 10.1016/j.chroma.2010.06.028

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Ketamine, a phencyclidine derivative, is used for induction of anesthesia, as an anesthetic drug for short term surgical interventions and in subanesthetic doses for postoperative pain relief. Ketamine undergoes extensive hepatic first-pass metabolism. Enantioselective capillary electrophoresis with multiple isomer sulfated -cyclodextrin as chiral selector was used to identify cytochrome P450 enzymes involved in hepatic ketamine and norketamine biotransformation in vitro. The N-demethylation of ketamine to norketamine and subsequently the biotransformation of norketamine to other metabolites were studied via analysis of alkaline extracts of in vitro incubations of racemic ketamine and racemic norketamine with nine recombinantly expressed human cytochrome P450 enzymes and human liver microsomes. Norketamine was formed by CYP3A4, CYP2C19, CYP2B6, CYP2A6, CYP2D6 and CYP2C9, whereas CYP2B6 and CYP2A6 were identified to be the only enzymes which enable the hydroxylation of norketamine. The latter two enzymes produced metabolic patterns similar to those found in incubations with human liver microsomes. The kinetic data of ketamine N-demethylation with CYP3A4 and CYP2B6 were best described with the Michaelis-Menten model and the Hill equation, respectively. This is the first study elucidating the individual enzymes responsible for hydroxylation of norketamine. The obtained data suggest that in vitro biotransformation of ketamine and norketamine is stereoselective.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery 05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Pharmacology and Toxicology 04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued]
UniBE Contributor:	Portmann, Simone, Kwan, Hiu, Schmitz, Andrea, Mevissen, Meike, Thormann, Wolfgang
ISSN:	0021-9673
Publisher:	Elsevier Science
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:09
Last Modified:	05 Dec 2022 14:00
Publisher DOI:	10.1016/j.chroma.2010.06.028
PubMed ID:	20609441
Web of Science ID:	000285429700003
URI:	https://boris.unibe.ch/id/eprint/839 (FactScience: 200986)