Biotransformation of ketamine in terminal in vivo experiments under chronic intermittent hypoxia conditions and the role of AhR
Year: 2025
Type: article
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.
Source: Archives of Toxicology
Authors: António B. Pimpão, Luísa Teixeira-Santos, Nuno R. Coelho, Maria João Correia, Judit Morello, Alexandra M. M. Antunes, Emília C. Monteiro, Sofia A. Pereira
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,690
Awards: Ahr: a therapeutic target for-morbidities associated with chronic intermittent hypoxia, G1516346500, G1570005492, G1578237752, Uma plataforma de Espetrometria de Massa e Machine Learning para combater a a Doença Crónica Renal e a Hipertensão Resistente: um guia para a estratificação de doentes e a aplicação de medicina de precisão, Via AhR-CYP1A1: integração da exposição ambiental e da apneia do sono para a optimização terapêutica da hipertensão arterial, G2578531282, Centro de Química Estrutural, Instituto de Ciências Moleculares, G3432522462, G3845776635, Use of a chronic intermittent hypoxia model to define the environmental cardiovascular risk associated with the aryl hydrocarbon receptor, NAT8 AS AN INDICATOR OF HYPERTENSION INDUCED BY EXPOSURE TO CHEMICALS AND INTERMITTENT HYPOXIA, G5454278309, iNOVA4Health - Programa de Medicina Translacional (iBET, CEDOC/FCM, IPOLFG e ITQB), G6412162175, G6696461781, Centro de Química Estrutural, G7858748947, G8685183387, G946021960
OpenAlex ID: W4409598249