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Contribution of Humanized Liver Chimeric Mice to the Study of Human Hepatic Drug Transporters: State of the Art and Perspectives

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Abstract

Chimeric mice with humanized livers constitute an attractive emergent experimental model for investigating human metabolism and disposition of drugs. The present review was designed to summarize key findings about the use of this model for studying human hepatic drug transporters, which are now recognized as important players in pharmacokinetics and consequently have to be considered from a regulatory perspective during pharmaceutical drug development. The reviewed data indicate that chimeric mice with humanized livers have been successfully used for analysing the implications of human hepatic drug transporters for drug hepatobiliary elimination, drug–drug interactions and drug-induced cholestasis. Such transporter studies have been performed in vivo with chimeric mice and/or in vitro with human hepatocytes isolated from humanized liver and used either in suspension or in culture. The residual presence of mouse hepatocytes and the potential morphological/histological alterations of the humanized liver, as well as its immunodeficient mouse environment, have, however, to be considered when using chimeric mice with humanized livers for transporter studies. Finally, if the proof of concept of applying chimeric mice with humanized livers to hepatic drug transport is established, more experimental data on this topic, including from standardization approaches, are likely required to completely and accurately demonstrate the robustness, convenience and added value of this chimeric mouse model for drug transporter studies.

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  1. University of Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000, Rennes, France

    Anna Zerdoug & Marc Le Vée

  2. Biopredic International, 35760, Saint Grégoire, France

    Anna Zerdoug, Béatrice Lopez & Christophe Chesné

  3. Central Institute for Experimental Animals, Kawasaki, 210-0821, Japan

    Shotaro Uehara & Hiroshi Suemizu

  4. University of Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043, Rennes, France

    Olivier Fardel

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Olivier Fardel conceived the review idea and the manuscript design and initiated the drafting and coordination. Anna Zerdoug collected and reviewed published data, elaborated the written sections, and prepared the article, figures and tables. Marc Le Vée, Shotaro Uehara, Béatrice Lopez, Christophe Chesné and Hiroshi Suemizu helped to draft and revise the manuscript. All authors read and approved the final manuscript.

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Zerdoug, A., Le Vée, M., Uehara, S. et al. Contribution of Humanized Liver Chimeric Mice to the Study of Human Hepatic Drug Transporters: State of the Art and Perspectives. Eur J Drug Metab Pharmacokinet 47, 621–637 (2022). https://doi.org/10.1007/s13318-022-00782-9

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