Investigation of Biotransformation Pathways in a Chimeric Mouse with a Humanized Liver

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• Accurate prediction of drug metabolism is essential for drug development.
• Current in vitro and animal models often fail to replicate human-specific metabolic pathways.
• Differences in biotransformation between species can impact drug efficacy and safety predictions.

Purpose of the Study:

• To evaluate the PXB-mouse model for its ability to mimic human drug metabolism.
• To assess the reliability of PXB-mice in predicting human metabolic profiles.
• To determine if human hepatocytes within the PXB-mouse liver can accurately predict human metabolic pathways.

Main Methods:

• Utilized PXB-mice, which possess livers engrafted with human hepatocytes (up to 95%).
• Evaluated the biotransformation of 12 small-molecule drugs in PXB-mice by analyzing blood and urine.
• Compared PXB-mouse metabolism data with human and mouse hepatocytes, and available human in vivo literature data.

Main Results:

• PXB-mice demonstrated metabolic patterns that closely aligned with human in vivo metabolism data.
• Major Phase I (e.g., hydroxylation) and Phase II (e.g., glucuronidation) metabolic transitions were detected.
• Human hepatocytes within the PXB-mouse liver were responsible for forming most circulating metabolites, confirming their predictive capability.

Conclusions:

• The PXB-mouse model effectively mimics human drug metabolic profiles.
• This model is valuable for predicting human-specific drug metabolism, especially for compounds with pathways not observed in nonclinical species.
• PXB-mice provide a reliable platform for assessing drug metabolism and safety prior to clinical trials.