Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. Here, the authors demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG mice) with humanized livers have a humanized biliary excretion profile of a test drug (cefmetazole). We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan, while liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. These results suggest that drug safety could be improved if preclinical toxicology studies included humanized TK-NOG mice.
See article at J Pharmacol Exp Ther 2015, 352:274–280.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics