Abstract
Drug-induced liver injury (DILI) remains a challenge in drug development, and interspecies differences in liver toxicity represent a need where comparative analyses may inform preclinical safety study design. In vitro testing for species-specific liver effects, especially in complex models such as microphysiological systems (MPS), may help predict toxicity before advancing from animal to human studies, or derisk spurious findings in preclinical species. This study assessed the utility of the perfusion-based PhysioMimix LC12 MPS as compared to 2D cultures and evaluated species-specific DILI using primary hepatocytes from human, monkey, rat, and dog. Functional, phenotypic, and transcriptional profiles were evaluated for up to 14 days. Also, cells were exposed to species-specific hepatotoxicants such as bosentan (BOS), fialuridine (FIAU), and a common hepatotoxicant for all species, chlorpromazine (CPZ)in both PhysioMimix LC12 and traditional 2D cultures. Hepatocytes in PhysioMimix LC12 showed more stable albumin and urea production as compared to 2D cultures. Concentration-response studies with CPZ, BOS, and FIAU were performed in 2D; then, repeated (5 × every 2 days) exposures to sub-100 × C max concentrations were tested in PhysioMimix LC12. Species-specific differences in cellular and molecular effects of the drugs were observed in both models; data from PhysioMimix LC12 were reflective of the expected effects in both animals and humans. Still, variability and low throughput are limitations of MPS for prospective studies of species-specific responses. Overall, this study confirms the utility of liver safety studies using PhysioMimix LC12 and also provides suggestions for experimental designs to overcome the limitations of more complex test systems.
Keywords:
PhysioMimix LC12; cross-species DILI; microphysiological system.