A Kenneth MacLeod, Kevin-Sebastien Coquelin, Leticia Huertas, Frederick R C Simeons, Jennifer Riley, Patricia Casado, Laura Guijarro, Ruth Casanueva, Laura Frame, Erika G Pinto, Liam Ferguson, Christina Duncan, Nicole Mutter, Yoko Shishikura, Colin J Henderson, David Cebrian, C Roland Wolf, Kevin D Read
A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice...
February 13, 2024: Proceedings of the National Academy of Sciences of the United States of America