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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
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Cytochrome P450s in chimeric mice with humanized liver.
Shotaro Uehara1, Hiroshi Suemizu1, Hiroshi Yamazaki2
1Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
Advances in Pharmacology (San Diego, Calif.)
|August 11, 2022
Summary
Humanized liver mice accurately model human drug metabolism and pharmacokinetics, producing human-like metabolites and enabling prediction of drug interactions. These models are valuable for drug development research.
Area of Science:
- Pharmacology
- Toxicology
- Biotechnology
Background:
- Chimeric mice with humanized livers offer a preclinical model for human drug metabolism.
- These models exhibit mature, functional human livers with zonal expression of cytochrome P450 enzymes.
- Gene expression patterns in humanized livers resemble those of mature human livers.
Purpose of the Study:
- To evaluate humanized liver mice as experimental models for drug metabolism and pharmacokinetic studies.
- To assess the comparability of drug oxidation activities between human and humanized liver mice.
- To investigate the utility of humanized liver mice for predicting human drug responses and interactions.
Main Methods:
- Comparison of P450-dependent drug oxidation activities in human and humanized liver microsomes.
- Analysis of metabolite profiles for P450 substrate drugs in humanized liver mice.
- Physiologically based pharmacokinetic modeling to extrapolate plasma concentration profiles.
- Investigation of drug-drug interactions using rifampicin induction and CYP2C9 inactivation models.
Main Results:
- Most P450-dependent drug oxidation activities were comparable, but variations in bufuralol and propafenone hydroxylation were noted.
- Human-specific metabolites of P450 substrate drugs were produced.
- Plasma concentration profiles in humans could be extrapolated from humanized liver mouse data.
- Hepatic CYP3A/2C induction and the role of CYP2C9 in diclofenac hydroxylation were successfully modeled.
Conclusions:
- Humanized liver mice serve as valuable experimental models for drug metabolism and pharmacokinetic studies.
- These models are effective for metabolite profiling, pharmacokinetic assessments, and drug interaction studies.
- The functional characteristics of hepatic human P450 enzymes are well-represented in these mice.
