Hepatotoxicity studies are an important part of the drug discovery process following lead molecule generation. Whereas the initial screening process identifies those molecules with target efficacy, hepatotoxicity studies uncover whether a potential drug induces drug-induced liver injury (DILI) in spite of any therapeutic effect.
While in vivo studies are still the gold standard; in vitro screening using primary hepatocytes, the cells predominantly responsible for the liver’s mass and metabolic functions, has gained importance for reducing animal exposure, amendable to high-throughput platforms and better equipped to determine toxicity mechanisms of action. Typically, this testing involves repeatedly dosing the hepatocytes with the potential drug over multiple days to assess cell viability and toxicity. However, the challenge remains in that hepatocytes cultured in traditional two-dimensional (2D) formats undergo rapid de-differentiation and loss of key functions. Additionally, 2D cultured cells are less able to form the cell-cell and cell-matrix communication networks seen in vivo4. Therefore, hepatotoxicity studies are usually limited in length, and results may not provide a complete understanding of the drug’s cumulative and long-term in vivo effects.