Journal
ARCHIVES OF TOXICOLOGY
Volume 94, Issue 8, Pages 2559-2585Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-020-02763-w
Keywords
Hepatotoxicity; Spheroid; HCI; DILI; Cmax; tot; Cmax; u; Strategies
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Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.
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