Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology
| Autor: | F. Peter Guengerich, Hiroshi Suemizu, Marina Mitsui, Hiroshi Yamazaki, Makiko Shimizu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Pharmacology Toxicology 030226 pharmacology & pharmacy Mass Spectrometry Article Activation Metabolic 03 medical and health sciences Mice 0302 clinical medicine Pharmacokinetics Cytochrome P-450 Enzyme System In vivo medicine Toxicokinetics Animals Humans media_common chemistry.chemical_classification biology Chemistry Chimera Cytochrome P450 General Medicine Thalidomide 030104 developmental biology Enzyme Liver biology.protein Drug metabolism medicine.drug |
| Zdroj: | Chemical research in toxicology. 29(12) |
| ISSN: | 1520-5010 |
| Popis: | 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 non-specific 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. |
| Databáze: | OpenAIRE |
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