CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity

Esketamine, the S-stereoisomer of (R,S)-ketamine was recently approved by drug agencies (FDA, EMA), as an antidepressant drug with a new mechanism of action. (R,S)-ketamine is a N-methyl-d-aspartate receptor (NMDA-R) antagonist putatively acting on GABAergic inhibitory synapses to increase excitatory synaptic glutamatergic neurotransmission. Unlike monoamine-based antidepressants, (R,S)-ketamine exhibits rapid and persistent antidepressant activity at subanesthetic doses in preclinical rodent models and in treatment-resistant depressed patients. Its major brain metabolite, (2R,6R)-hydroxynorketamine (HNK) is formed following (R,S)-ketamine metabolism by various cytochrome P450 enzymes (CYP) mainly activated in the liver depending on routes of administration [e.g., intravenous (largely used for a better bioavailability), intranasal spray, intracerebral, subcutaneous, intramuscular or oral]. Experimental or clinical studies suggest that (2R,6R)-HNK could be an antidepressant drug candidate. However, questions still remain regarding its molecular and cellular targets in the brain and its role in (R,S)-ketamine's fast-acting antidepressant effects. The purpose of the present review is: 1) to review (R,S)-ketamine pharmacokinetic properties in humans and rodents and its metabolism by CYP enzymes to form norketamine and HNK metabolites; 2) to provide a summary of preclinical strategies challenging the role of these metabolites by modifying (R,S)-ketamine metabolism, e.g., by administering a pre-treatment CYP inducers or inhibitors; 3) to analyze the influence of sex and age on CYP expression and (R,S)-ketamine metabolism. Importantly, this review describes (R,S)-ketamine pharmacodynamics and pharmacokinetics to alert clinicians about possible drug-drug interactions during a concomitant administration of (R,S)-ketamine and CYP inducers/inhibitors that could enhance or blunt, respectively, (R,S)-ketamine's therapeutic antidepressant efficacy in patients.