Early toxicology signal generation in the mouse
| Autor: | Xuemei Liu, Jeffrey A. Kramer, William Heydorn, Bobby Joe Payne, Xiang-Qing Yu, Megan E. Phillips, Emily O’Neill, Amr Nouraldeen, Debra Bruce, Sairam Bellum, Peter Vogel, Suma Gopinathan, Alan Wilson, Melinda M. Albright, R. Read, Traci Smith |
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| Rok vydání: | 2010 |
| Předmět: |
Prioritization
Male Rodent biology Antineoplastic Agents Cell Biology Toxicology Oral gavage Pathology and Forensic Medicine Rats Sprague dawley Toxicology studies Mice Inbred C57BL Rats Sprague-Dawley Experience base Disease Models Animal Mice In vivo biology.animal Toxicity Tests Animals Enzyme Inhibitors Molecular Biology |
| Zdroj: | Toxicologic pathology. 38(3) |
| ISSN: | 1533-1601 |
| Popis: | The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project’s life cycle. |
| Databáze: | OpenAIRE |
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