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Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology

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† Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
‡ Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan
§ Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
*Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. Tel: +81-42-721-1406. Fax: +81-42-721-1406. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2016, 29, 12, 1903–1911
Publication Date (Web):June 23, 2016
https://doi.org/10.1021/acs.chemrestox.6b00136
Copyright © 2016 American Chemical Society
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    Abstract

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    Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated 14C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.

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    • Parameters for simplified PBPK models for caffeine, warfarin, omeprazole, metoprolol, and midazolam (PDF)

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