Understanding Mechanisms of Drug-Induced Liver Injury Using Primary Human Cell and Co-culture Systems

Understanding Mechanisms of Drug-Induced Liver Injury Using Primary Human Cell and Co-culture Systems
Version:
2014

File Name/Number:
Society of Toxicology

Year:
2014

Drug induced liver injury, in particular the idiosyncratic type (IDILI), is extremely difficult to identify before a compound reaches the later stages of drug development, often not being detected until the clinical trials or when the drug is approved and in the market. Well known examples of drugs causing IDILI include the anti-diabetic drug, troglitazone, the monoamine oxidase inhibitor, iproniazid, and the non-steroidal antiinflammatory drugs (NSAIDS), bromfenac. Drugs with potential for IDILI put the lives of patients at significant risk. Also, withdrawals of these lucrative drugs diminish the return on substantial investments by drug makers and threaten further R&D. Hence, elucidating the mechanisms by which DILI occurs early in drug discovery is an important focus of pharmaceutical research.

In the present study, we investigated feasibility of the BioMAP (part of DiscoveRx) technology platform to understand the mechanisms of DILI of marketed drugs using primary human cells, stimulated under a variety of conditions mimicking disease biology. A total of 63 compounds from Most-DILI (41) and No-DILI (22) category1, a majority of which are part
of Phase-II of EPA’s ToxCast initiative2, were profiled in eight Biomap primary human cell systems at 4 different concentrations using combination of endothelial, epithelial, smooth muscle, keratinocytes and fibroblasts cells, measuring a total of 86 protein readouts and generating over 21000 data points.