In vitro characterization of the drug metabolizing capacity of hepatocytes from MASH livers and development of a PK model for MASH patients

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver damage worldwide. MASLD is characterized by excess lipid accumulation in hepatocytes (>5%) and can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which is characterized by steatosis, inflammation and fibrosis. MASLD/MASH is often associated with the metabolic syndrome, hence, patients with metabolic dysregulations are more susceptible for MASLD/MASH formation. Currently, there are no FDA-approved pharmacological drugs available for the therapy of MASLD/MASH, as well as no accurate pharmacokinetic predictions for those patients.

Our aim is to establish a PK model supporting future clinical studies, drug research and dose adjustments in therapy or co-medication of MASH patients. The model will be based on in-depth characterization of hepatocytes and non-parenchymal cells in MASH and healthy state from human and rodents applying different in vitro and in vivo systems. Initially, we investigated drug metabolizing enzymes and liver-specific parameters of primary human hepatocytes (PHHs) in 2D suspension culture, 2.5D sandwich culture and the commercially 3D InSight™ Human Liver Co-Culture MASH Model (InSphero AG).

We observed changes in mRNA and protein expression as well as activity of drug metabolizing enzymes in healthy vs. MASH diseased cells. Liver-specific parameters also differentiate in healthy and MASH donors. Nonetheless, it has to be considered that there is a high donor variability in the 2D suspension culture system why more complex models (2.5D and 3D culture) should help to prevent such high donor variabilities by comparing a healthy and MASH diseased state from the same donor.

Publication History

Article published online:
20 January 2025