NDLI: Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

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Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

Content Provider	Springer Nature Link
Author	Dragovic, Sanja Vermeulen, Nico P. E. Gerets, Helga H. Hewitt, Philip G. Ingelman‐Sundberg, Magnus Park, B. Kevin Juhila, Satu Seys, Jan Weaver, Richard J.
Copyright Year	2016
Abstract	The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.
Starting Page	2979
Ending Page	3003
Page Count	25
File Format	PDF
ISSN	03405761
Journal	Archives of Toxicology
Volume Number	90
Issue Number	12
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-09-22
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Drug-induced liver injury (DILI) MIP-DILI Set of training compounds Evidence-based selection DILI mechanisms Pharmacology/Toxicology Occupational Medicine/Industrial Medicine Environmental Health Biomedicine
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology

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Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

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Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

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Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man