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

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.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Dragovic S,Vermeulen NP,Gerets HH,Hewitt PG,Ingelman-Sundberg M,Park BK,Juhila S,Snoeys J,Weaver RJ

doi

10.1007/s00204-016-1845-1

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

2979-3003

issue

12

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-016-1845-1

journal_volume

90

pub_type

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