Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

Autor: Loan Nguyen TM; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France., Guilloux JP; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France., Defaix C; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France., Mendez-David I; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France., Etting I; Service de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Groupe Hospitalier Universitaires AP-HP, Université Paris-Saclay, Inserm U-1018, CESP, MOODS Team, 92380 Garches, France., Alvarez JC; Service de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Groupe Hospitalier Universitaires AP-HP, Université Paris-Saclay, Inserm U-1018, CESP, MOODS Team, 92380 Garches, France., McGowan JC; Department of Psychiatry, Columbia University, New York, NY, 10032, USA; Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) /New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA., Highland JN; Departments of Psychiatry, Baltimore, MD, USA; Departments of Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD, USA; Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA., Zanos P; Departments of Psychiatry, Baltimore, MD, USA; Departments of Pharmacology, Baltimore, MD, USA; Departments of Physiology, Baltimore, MD, USA; Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Department of Psychology, University of Cyprus, Nicosia, 2109, Cyprus., Lovett J; Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Moaddel R; Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Corruble E; Université Paris-Saclay, Faculté de Médecine, Inserm UMR 1018, CESP, MOODS Team, 94270 Bicêtre Hospital, 94270 Le Kremin-Bicêtre, France; Service Hospitalo-Universitaire de Psychiatrie de Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Saclay, Hôpital de Bicêtre, 94270 Le Kremlin Bicêtre, France., David DJ; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France., Gould TD; Departments of Psychiatry, Baltimore, MD, USA; Departments of Pharmacology, Baltimore, MD, USA; Departments of Physiology, Baltimore, MD, USA; Departments of Neurobiology, Baltimore, MD, USA; Departments of Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD, USA; Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA; Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Denny CA; Department of Psychiatry, Columbia University, New York, NY, 10032, USA; Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) /New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA., Gardier AM; Université Paris-Saclay, Faculté de Pharmacie, Inserm UMR 1018, CESP, MOODS Team, 91400 Orsay, France. Electronic address: alain.gardier@universite-paris-saclay.fr.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Nov 01; Vol. 258, pp. 110065. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1016/j.neuropharm.2024.110065
Abstrakt: (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 (Glu ext , GABA ext ) 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.
Competing Interests: Declaration of competing interest DJD serves as a consultant for Lundbeck, Roche, and Servier. AMG serves as a consultant for Lundbeck and Servier. JM, IM-D, DJD, AMG, and CAD are named on provisional patent applications for the prophylactic use of ketamine and other compounds against stress-related psychiatric disorders. PZ, JH, RM, and TDG are co-inventors in patents and/or patent applications related to the pharmacology and synthesis, crystal structure and use of HNKs and related molecules for the treatment of addiction, depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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