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Updated: May 28, 2025
Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells
Published on: August 29, 2016
Investigation of Biotransformation Pathways in a Chimeric Mouse with a Humanized Liver
Isabella B Karlsson1, Anja Ekdahl1, Hugh Etchingham-Coll1
1Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
Abstract:
Xenobiotics, including drugs, undergo metabolism to facilitate detoxification and excretion. Predicting a compound's metabolic fate before clinical trials is crucial for efficacy and safety. The existing methods rely on in vitro systems and in vivo animal testing. In vitro systems do not replicate the complexity of in vivo systems, and differences in biotransformation pathways between humans and nonclinical species may occur; thus, accurate predictions of human-specific drug metabolism are not always achieved. The aim of this study was to evaluate whether a chimeric mouse with a humanized liver, specifically the PXB-mouse, can mimic human metabolic profiles. PXB-mice have livers engrafted with up to 95% human hepatocytes. The biotransformation of 12 different small-molecule drugs were evaluated in PXB-mice (through analysis of blood and urine) and compared with the metabolism by hepatocytes from humans and mice and, when available, literature reports on human in vivo metabolism. The detected metabolites included major Phase I and II transitions, such as hydroxylation, and N- and O-dealkylation and glucuronidation. The metabolic patterns of the PXB-mice closely matched human in vivo data. It is also worth noting that the human hepatocytes formed most of the circulating metabolites, indicating that hepatocytes provide reliable predictions of human metabolic pathways. Thus, for drugs with human biotransformation pathways that are not observed in nonclinical species, the PXB-mouse model can be valuable in predicting human-specific metabolism.
Insights
Predicting drug metabolism is vital for safety. A humanized liver mouse model (PXB-mouse) closely mimics human drug metabolism, offering a valuable tool for predicting metabolic fate before clinical trials.
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.
