Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies

Abstract

1. Immunocompromised mice with humanized livers were developed in the mid-1990s to allow the study of human hepatotropic viruses, which normally replicate only in higher primates. The production of the uPA/SCID mouse was the vanguard of these models and remains the most widely worked upon model for an ever increasing range of applications.

2. Since toxicology is conducted in laboratory animal species with the implicit intent of predicting the outcome of accidental, or intentional, human exposure, the potential for using an in vivo model with a humanised metabolism opens up the possibility of better predicting the human response following exposure to drugs and industrial chemicals. Chimeric humanised mice provide the tool for bridging between the non-clinical laboratory safety and metabolism studies, carried out in rodent and non-rodent species, and the first in man clinical trials.

3. Chimeric mice carrying a human liver have now been validated against a wide range of different drugs and chemical classes, and have been shown to clearly differentiate metabolically from the recipient mouse, and to show metabolic pathways more similar to those expected from human liver.

4. This review critically appraises the available animal models carrying human livers and where future developments would improve the existing systems.

• Animal to human extrapolation
• cytochrome P450
• DMPK
• FRG mouse
• hepatotoxicity
• metabolism
• TK-NOG mouse
• uPA/SCID mouse