University of Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35000, Rennes, France.
Biopredic International, 35760, Saint Grégoire, France.
Eur J Drug Metab Pharmacokinet. 2022 Sep;47(5):621-637. doi: 10.1007/s13318-022-00782-9. Epub 2022 Jul 6.
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.
嵌合小鼠的人类肝脏构成有吸引力的新兴实验模型，用于研究人类新陈代谢和药物处置。本综述旨在总结关于使用这种模型来研究人类肝药物转运体的关键发现，这些转运体现在被认为是药代动力学中的重要参与者，因此在药物开发过程中必须从监管角度考虑。综述数据表明，嵌合小鼠的人类肝脏已成功用于分析人类肝药物转运体对药物肝胆消除、药物相互作用和药物诱导的胆汁淤积的影响。这些转运体研究已在体内进行，使用嵌合小鼠，并/或在体外用人源化肝脏分离的人肝细胞进行，无论是在悬浮液中还是在培养中进行。然而，在使用具有人源化肝脏的嵌合小鼠进行转运体研究时，必须考虑到小鼠肝细胞的残留存在以及人源化肝脏的潜在形态/组织学改变，以及其免疫缺陷的小鼠环境。最后，如果证明将具有人源化肝脏的嵌合小鼠应用于肝药物转运是合理的，那么可能需要更多关于该主题的实验数据，包括标准化方法，以完全和准确地证明这种嵌合小鼠模型在药物转运体研究中的稳健性、便利性和附加值。
