Metabolism and metabolomics of ketamine: a toxicological approach

Ketamine, a dissociative anesthetic, is metabolized primarily in the liver by cytochrome P450 enzymes, especially 3A4 and 2B6, into the active metabolite norketamine and other minor compounds. Recent metabolomics studies show ketamine alters glycolysis, the tricarboxylic acid cycle, amino acid metabolism, and mitochondrial fatty acid oxidation. Understanding these metabolic pathways may improve clinical and forensic characterization of ketamine.

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Abstract

ABSTRACT Ketamine is a phencyclidine derivative and a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor for which glutamate is the full agonist. It produces a functional dissociation between the thalamocortical and limbic systems, a state that has been termed as dissociative anaesthesia. Considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile has been reported. This review aims to discuss pharmacokinetics of ketamine, namely focusing on all major and minor, active and inactive metabolites. Both ketamine optical isomers undergo hepatic biotransformation through the cytochrome P450, specially involving the isoenzymes 3A4 and 2B6. It is first N-demethylated to active metabolite norketamine. Different minor pathways have been described, namely hydroxylation of the cyclohexanone ring of ketamine and norketamine, and further conjugation with glucuronic acid to increase renal excretion. More recently, metabolomics data evidenced the alteration of several biological pathways after ketamine administration such as glycolysis, tricarboxylic acid cycle, amino acids metabolism and mitochondrial β-oxidation of fatty acids. It is expected that knowing the metabolism and metabolomics of ketamine may provide further insights aiming to better characterize ketamine from a clinical and forensic perspective.