Application of chimeric mice with humanized liver for predictive ADME

Area of Science:

• Pharmacology and Toxicology
• Biotechnology
• Genetics

Background:

• Extrapolating in vivo pharmacokinetics from animal models to humans is challenging.
• Human liver is critical for drug metabolism and pharmacokinetics (ADME).
• Existing in vitro models using human hepatocytes and microsomes have limitations.

Purpose of the Study:

• To evaluate a novel chimeric mouse model with a humanized liver for drug ADME studies.
• To assess the predictive capacity of this model for human drug metabolism and interactions.
• To determine if the model can accurately reflect human drug excretion pathways.

Main Methods:

• Utilized a urokinase-type plasminogen activator (uPA) transgenic mouse line engrafted with human hepatocytes.
• Assessed expression and activity of human phase I and II drug-metabolizing enzymes.
• Evaluated drug metabolism, enzyme induction/inhibition, and drug excretion in chimeric mice.
• Compared drug disposition in chimeric mice with control mice and human data.

Main Results:

• Human hepatocytes replaced over 80% of the liver in chimeric mice.
• Human drug-metabolizing enzymes (CYP1A2, CYP3A4, CYP2D6) were expressed and functional.
• Chimeric mice exhibited human-specific metabolites and predicted drug interactions (induction and inhibition).
• Drug excretion patterns in chimeric mice mimicked human excretion.

Conclusions:

• Chimeric mice with humanized livers serve as a valuable in vivo model for predicting human drug ADME.
• This model facilitates more accurate drug development by simulating human drug metabolism and interactions.
• The model shows promise for both in vitro and in vivo drug assessment and interaction studies.