Comparative Analysis of Species-Specific Hepatocyte Function and Drug Effects in a Liver Microphysiological System PhysioMimix® LC12 and 96-Well Plates

ABSTRACT: Drug-induced liver injury (DILI) remains a major challenge in drug development and inter-species differences in potential liver toxicity are one area where comparative analyses may inform pre-clinical 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 de-risk spurious findings in pre-clinical species. This study assessed the utility of the perfusion-based PhysioMimix® LC12 MPS for evaluating species-specific DILI using primary hepatocytes from human, monkey, rat, and dog. First, functional, phenotypic, and transcriptional profiles were established over 2 weeks in cell culture. Then, cells were exposed to species-specific DILI compounds – chlorpromazine (CPZ), bosentan (BOS), and fialuridine (FIAU) – in both PhysioMimix® LC12 and traditional 2D cultures. Hepatocytes in PhysioMimix® LC12 showed more stable albumin and urea production for up to 14 days as compared to 2D cultures. Concentration-response studies with CPZ, BOS, or FIAU were performed in 2D; then, prolonged exposures (10 days) to sub-100× Cmax 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 more reflective of the expected effects in whole animals or humans. Still, variability and low throughput are limitations of the MPS for prospective studies of species-specific responses. Overall, this study confirms the utility of liver safety studies using MPS, but also provides suggestions for experimental designs to overcome the limitations of more complex test systems.

ORGANISM(S): Rattus norvegicus Canis lupus familiaris Homo sapiens Macaca fascicularis

PROVIDER: GSE300171 | GEO | 2025/12/04

REPOSITORIES: GEO