ArticleDrug metabolism and disposition: the biological fate of chemicals2019
An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Predictability of human exposure by human-CYP3A4-transgenic mouse models: A meta-analysis.Clinical and translational science · 2024Pooled it
- Applications of humanized mice inMolecular medicine reports · 2026Review
- Stereoselective Biotransformation: Transfer of Learning to Advance Drug Metabolism and Biocatalysis.Angewandte Chemie (International ed. in English) · 2026Review
- Use of a cytochrome P450 humanized mouse model to refine schistosomiasis drug discovery.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Humanization of Drug Metabolism in theACS infectious diseases · 2025Article
- Application of a mouse model humanized for cytochrome P450-mediated drug metabolism to predict drug-drug interactions between a peptide and small molecule drugs.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals.Archives of toxicology · 2025Article
- Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment.Biomolecules · 2024Review
- Rethinking our approach to cancer metabolism to deliver patient benefit.British journal of cancer · 2023Review
- Multiple genome viewer (MGV): a new tool for visualization and comparison of multiple annotated genomes.Mammalian genome : official journal of the International Mammalian Genome Society · 2022Article
- Improving the predictive power of xenograft and syngeneic anti-tumour studies using mice humanised for pathways of drug metabolism.F1000Research · 2022Article
- Assessing cytochrome P450 function using genetically engineered mouse models.Advances in pharmacology (San Diego, Calif.) · 2022Review
- Human Somatostatin SSTInternational journal of molecular sciences · 2021Article
- The pursuit of precision mitochondrial medicine: Harnessing preclinical cellular and animal models to optimize mitochondrial disease therapeutic discovery.Journal of inherited metabolic disease · 2021Review
- Cross-species analysis of hepatic cytochrome P450 and transport protein expression.Archives of toxicology · 2021Article
- Defining the Contribution of CYP1A1 and CYP1A2 to Drug Metabolism Using Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 Knockout Mice.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PK data to man and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create a mouse model that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.