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Drug Metab Dispos. 2018 Nov;46(11):1658-1669. doi: 10.1124/dmd.118.082719. Epub 2018 Jul 18.

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

Author information

1
Safer Medicines Trust, Kingsbridge, United Kingdom (J.G.K.); and Faculties of Pharmacy and Medicine, University of Toronto, Toronto, Ontario, Canada (J.U.).
2
Safer Medicines Trust, Kingsbridge, United Kingdom (J.G.K.); and Faculties of Pharmacy and Medicine, University of Toronto, Toronto, Ontario, Canada (J.U.) jack.uetrecht@utoronto.ca.

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 predictive assays unless those parameters are actually involved in the mechanism of iDILI. Hence, a better mechanistic understanding of iDILI is required; however, mechanistic studies of iDILI are very difficult. There is substantive evidence that most iDILI is immune mediated; therefore, the most accurate assays may involve those that determine immune responses to drugs. New methods to manipulate immune tolerance may greatly facilitate development of more suitable methods.

PMID:
30021844
DOI:
10.1124/dmd.118.082719

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