Predictive toxicity assessment is a critical initial task for most in vitro evaluation programs. Results from the toxicity assessment inform lead selection decisions, help determine the dose range for subsequent assessments, and provide baseline information critical to understanding the effect of the test compound in the model. We recommend using human hepatocytes models for in vitro predictive tox studies because of their improved IVIVC compared to in vivo animal models or other systems. Additionally, we conduct toxicity studies using other species for cross-species comparison studies.
Based on the study objectives and characteristics of the compounds being investigated we design programs that include the following physiologically-relevant models for predictive tox assessments:
- HEPATOPAC Cultures
- TRANSPORTER CERTIFIED hepatocytes in sandwich culture
- Plated hepatocytes
We use HEPATOPAC Technology to create stable hepatocyte cultures that can remain viable for up to 28 days. We recommend HEPATOPAC cultures for long-term (>72hrs) toxicity studies, repeat dosing studies, and studies to investigate compounds that exhibit delayed toxicity. HEPATOPAC cultures have been demonstrated to have improved sensitivity and specificity for in vitro DILI detection compared to other models.
TRANSPORTER CERTIFIED Hepatocytes in Sandwich Culture
TRANSPORTER CERTFIED™ hepatocytes express biliary efflux transporters when cultured in sandwich culture under conditions we have defined. We recommend use of the TRANSPORTER CERTIFIED hepatocyte model in sandwich culture to investigate compounds that are cleared through active biliary transporters. Biliary excretion can reduce intracellular concentration of a compound and impact the dose rate for cytotoxicity and other studies.
In this model we typically we evaluate toxicity after 24 or 72 hours of exposure to the compound. In our typical experimental design, we include seven concentrations of the test compound ranging from Cmax, to 50X Cmax and include a vehicle and positive control. We assess cell viability based on ATP present in treated vs. untreated cells.
As industry leaders in the development of hepatocyte technology and cryopreservation, BioIVT provides the greatest selection and the largest lot sizes of hepatocytes to aid in your research. We recommend plated hepatocytes, including use of our LIVERPOOL hepatocytes for predictive toxicity study which do not require long-term cultures and biliary efflux is not thought to be an important route of excretion.