Biotransformation of ketamine in terminal in vivo experiments under chronic intermittent hypoxia conditions and the role of AhR.

Chronic intermittent hypoxia (CIH), which models the low-oxygen episodes of obstructive sleep apnea, alters how the body processes ketamine, a common anesthetic. In rats exposed to CIH, a shift in ketamine metabolism favored hydroxynorketamine over norketamine in liver and kidney tissues. Six metabolites were identified, including the first report of norketamine glucuronide formation in the liver. Blocking the aryl hydrocarbon receptor (AhR) with an antagonist changed hydroxynorketamine glucuronidation, suggesting AhR overactivation in CIH influences ketamine breakdown. These findings highlight that anesthetic metabolism can differ under disease conditions like sleep apnea, emphasizing the need to account for such changes in metabolic studies.

Study at a glance

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.