Biotransformation of ketamine in terminal in vivo experiments under chronic intermittent hypoxia conditions and the role of AhR.
António B Pimpão, Luísa Teixeira-Santos, Nuno R Coelho, Maria João Correia, Judit Morello, Alexandra M M Antunes, Emília C Monteiro, Sofia A Pereira
Archives of Toxicology April 19, 2025 DOI: 10.1007/s00204-025-04044-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pre-clinical animal study Longitudinal Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine/medetomidine CH-223191 |
| Dose | 75/0.5 mg/kg (ketamine/medetomidine); 5 mg/kg (CH-223191) |
| Topics | Esketamine Ketamine |
| Keywords | Aryl hydrocarbon receptor Hydroxynorketamine Norketamine glucuronide Obstructive sleep apnea Drug metabolism Anesthesia safety Ketamine processing Oxygen levels |
| Key points | Chronic intermittent hypoxia shifts ketamine metabolism toward hydroxynorketamine over norketamine, and the aryl hydrocarbon receptor plays a role in this biotransformation. |
Abstract
We were pioneers in describing aryl hydrocarbon receptor (AhR) activation by chronic intermittent hypoxia (CIH) in a rat pre-clinical model. This model mimics hypertension (HTN) secondary to obstructive sleep apnea, enabling longitudinal investigation of hypertension development. Concerns about the influence of barbiturates on AhR-regulated enzymes led us to opt for ketamine/medetomidine anesthesia in terminal in vivo experiments. However, the biotransformation and the metabolomic pathways of ketamine in CIH conditions, which is associated to AhR overactivation, are yet to be disclosed. A rat model of CIH was used, with experimental groups defined based on the duration of CIH exposure. Ketamine/medetomidine (75/0.5 mg/kg) was administered intraperitoneally as terminal anesthetic. Metabolomic strategies were used to reveal the profiles of ketamine and its metabolites in liver and kidney tissues, uncovering six metabolites, including the first report of norketamine glucuronide formation in the liver. While PCA analysis revealed similar ketamine metabolite fingerprints in normoxia and CIH, a predominance of hydroxynorketamine over norketamine was observed in CIH condition. A consistent association between norketamine, hydroxyketamine and the metabolome was found in both normoxia and CIH conditions. The AhR antagonist CH-223191 (5 mg/kg) influenced hydroxynorketamine glucuronidation in the liver. No changes in medetomidine biotransformation were detected. Overall, these findings expand the knowledge of ketamine metabolism and its tissue-dependence. The results emphasize the importance of considering how ketamine biotransformation may differ between control and experimental conditions in metabolic studies, particularly in chronic intermittent hypoxia conditions. The role of AhR in ketamine biotransformation is herein described for the first time.
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 6
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? The Journal of Clinical Psychiatry July 20, 2017
and 1 more in the library