Troglitazone metabolism and transporter effects in chimeric mice: a comparison between chimeric humanized and...

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• Troglitazone, a drug previously used for type 2 diabetes, was withdrawn due to liver toxicity.
• Understanding its metabolic pathways and effects in vivo is crucial for drug development.
• Chimeric mouse models offer a platform to study human drug metabolism.

Purpose of the Study:

• To investigate the biotransformation, hepatic transporter, and blood chemistry effects of troglitazone.
• To compare troglitazone metabolism in mouse models with varying degrees of humanization.
• To assess the utility of chimeric mice for predicting human drug metabolism.

Main Methods:

• Administration of troglitazone (600 mg/kg/day for 7 days) to chimeric murinized (Mo-FRG) and humanized (Hu-FRG) mice.
• Clinical chemistry, histopathology, and transporter expression analysis.
• Metabolite profiling in blood and bile to identify oxidative and conjugative pathways.

Main Results:

• A significant decrease in humanization was observed in Hu-FRG mice over the study period.
• No significant changes in clinical chemistry or transporter expression were linked to troglitazone treatment in either model.
• A 15- to 18-fold increase in troglitazone sulfate formation was observed in Hu-FRG mice compared to Mo-FRG mice, mimicking human metabolism.
• Increased troglitazone glucuronide was also noted in Hu-FRG mice, potentially related to decreased humanization.

Conclusions:

• Highly humanized chimeric mice provide valuable initial insights into circulating human drug metabolites.
• Troglitazone metabolism in Hu-FRG mice, particularly sulfate conjugate formation, resembles human metabolic profiles.
• Chimeric mouse models are promising tools for preclinical drug metabolism studies.