Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Abstract

Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Figures

Fig. 1.

Major metabolic pathways. In the predominant metabolic pathway, racemic ketamine [(R,S)-KET] is initially metabolized to norketamine [(R,S)-norKET], by either CYP2B6 or CYP3A4. Subsequently, norketamine can be further metabolized to form DHNK or the HNKs. Hydroxylation of norketamine at the six position by CYP2A6 results in (2R,6S;2S,6S)-hydroxynorketamine [(2R,6R;2S,6S)-HNK]. Alternatively, CYP2B6 or CYP2A6 can hydroxylate norketamine at the four position, resulting in the 4-hydroxy isomers. In the third case, CYP2B6 can hydroxylate norketamine at the five position, resulting in (2R,5S;2S,5R)-HNK and (2R,5R;2S,5S)-HNK. (R,S)-DHNK can result either from direct dehydrogenation from norketamine via CYP2B6 or via dehydration from either diastereomer of the 5-hydroxynorketamines via a nonbiologically catalyzed process.

Fig. 2.

Minor metabolic pathways. Although the majority of ketamine is metabolized via the major metabolic pathways (Fig. 1), there are several minor metabolic pathways, which provide unique, albeit low abundance, ketamine metabolites. The aryl ring of ketamine can be directly hydroxylated by flavin-containing mono-oxygenase enzymes or CYP2C9 to provide hydroxyphenyl-ketamine (hydroxyphenyl-KET). 4-Hydroxyketamine has also been observed; however, the metabolic enzymes responsible for this are currently unknown. CYP3A5 can directly hydroxylate ketamine at the six position to provide (2R,6S;2S,6R)-HK. Demethylation of (2R,6S;2S,6R)-HK with CYP3A5 provides (2R,6S;2S,6R)-HNK. CYP2A6 can also directly hydroxylate ketamine to provide (2R,6R;2S,6S)-HK, which is then transformed to (2R,6R;2S,6S)-HNK. Finally, norketamine can be hydroxylated via an unknown enzyme directly on the aryl rich to provide hydroxyphenyl-norketamine (hydroxyphenyl-norKET).