Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix, Indira Mendez-David, Isabelle Etting, Jean-Claude Alvarez, Josephine C McGowan, Jaclyn N. Highland, Panos Zanos, Jacqueline Lovett, Ruin Moaddel, Emmanuelle Corruble, Denis J David, Todd D Gould, Christine A Denny, Alain M. Gardier
Neuropharmacology November 1, 2024 DOI: 10.1016/j.neuropharm.2024.110065 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with pretreatment and behavioral/neurochemical measures Peer reviewed |
|---|---|
| Population | Male BALB/cJ mice with a highly anxious phenotype |
| Interventions | Fluconazole Ketamine (2R 6R)-hydroxynorketamine |
| Dose | 10 and 20 mg/kg fluconazole; 10 mg/kg ketamine or HNK |
| Duration | 24 hours post-injection |
| Topics | Esketamine Ketamine |
| Keywords | R,s-ketamine Cytochrome p450 inhibitor Fluconazole Gaba Glutamate Hnk Hydroxynorketamine Medial prefrontal cortex Microdialysis Rapid-acting antidepressant Ketamine metabolism Antidepressant mechanisms Neuropharmacology Liver enzymes |
| Citations | 3 |
| Key findings | Inhibiting cytochrome P450 with fluconazole reduced HNK levels and blocked ketamine's sustained antidepressant-like effects, which were restored by administering (2R,6R)-HNK alone. |
Abstract
(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 13
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine Proceedings of the National Academy of Sciences December 17, 2018
- Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression British Journal of Clinical Pharmacology February 1, 2012
and 8 more in the library