Hepatocytes - "Investigating DILI using MetaHeps cells on Nanion’s CardioExcyte 96"
Drug Induced Liver Injury (DILI) is the major cause of acute liver failure in the USA and Europe and is one of the main reasons for regulatory actions and market withdrawals. Indeed, hepatic toxicity has accounted for 15 of the 47 drugs withdrawn from the market in the period 1975 - 2007. DILI is classified as intrinsic or dosedependent, acetaminophen (paracetamol) being the most important example of this class, or idiosyncratic which is unpredictable and not directly dependent on dose. A number of factors contribute to an individual’s susceptibility to develop idiosyncratic DILI including age, sex, alcohol consumption, drug interactions and genetic variability. Although improvements have been made to cellular and animal models to predict intrinsic (dose-dependent) DILI, it is almost impossible to predict idiosyncratic DILI. Withdrawal of compounds at a late stage (or postmarketing) due to idiosyncratic DILI is costly and can lead to incorrect withdrawal of potentially useful compounds. Monocyte-derived hepatocyte-like (MH) cells have been developed as a tool to investigate longterm hepatotoxicity, metabolism and drug interactions. Furthermore, patient-derived MH cells could provide a tool for diagnosis or exclusion of idiosyncratic DILI and provide the causative agent in polymedicated patients.
In this study, MH cells (MetaHeps®) were used on the CardioExcyte 96 and changes in impedance, and therefore confluency, were used as a measure of toxicity. Intrinsic (dose-dependent) effects of paracetamol could be identified consistent with other methods of liver injury detection. Therefore, the CardioExcyte 96 in combination with patient-specific MH cells provides a novel tool for investigating intrinsic and idiosyncratic DILI.