Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk?

Drug Metabolism and Disposition : the Biological Fate of Chemicals
J Gerry Kenna, Jack Uetrecht

Abstract

In vitro assays are commonly used during drug discovery to try to decrease the risk of idiosyncratic drug-induced liver injury (iDILI). But how effective are they at predicting risk? One of the most widely used methods evaluates cell cytotoxicity. Cytotoxicity assays that used cell lines that are very different from normal hepatocytes, and high concentrations of drug, were not very accurate at predicting idiosyncratic drug reaction risk. Even cytotoxicity assays that use more biologically normal cells resulted in many false-positive and false-negative results. Assays that quantify reactive metabolite formation, mitochondrial injury, and bile salt export pump (BSEP) inhibition have also been described. Although evidence suggests that reactive metabolite formation and BSEP inhibition can play a role in the mechanism of iDILI, these assays are not very accurate at predicting risk. In contrast, inhibition of the mitochondrial electron transport chain appears not to play an important role in the mechanism of iDILI, although other types of mitochondrial injury may do so. It is likely that there are many additional mechanisms by which drugs can cause iDILI. However, simply measuring more parameters is unlikely to provide better predic...Continue Reading

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Citations

Oct 20, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aarti Sawant-Basak, R Scott Obach
Nov 14, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Hiroshi KoharaTadahiro Shinozawa
Apr 24, 2020·Expert Opinion on Drug Metabolism & Toxicology·Robert A Roth, Patricia E Ganey
Feb 9, 2020·Toxicology and Applied Pharmacology·Giulio GiustariniRaymond H H Pieters
Mar 19, 2021·Frontiers in Cell and Developmental Biology·Ana S SerrasJoana P Miranda
Apr 4, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Thomas J DiProsperoMatthew R Lockett
May 22, 2021·In Silico Pharmacology·Vaibhav A Dixit, Pragati Singh
Sep 10, 2019·Journal of Medicinal Chemistry·Amit S Kalgutkar

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