Abstract

Due to the substantial inter-species differences in drug metabolism and drug disposition, drug-induced liver injury (DILI) 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 pre-clinical toxicology studies in multiple animal species. Here, we demonstrate that TK-NOG mice with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from inter-species differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after one week of treatment with bosentan (160, 32 or 6 mg/kg/day PO), while liver toxicity did not develop in control mice after one month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Since DILI has become a significant public health problem, drug safety could be improved if pre-clinical toxicology studies were performed using humanized TK-NOG.