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Expert Opin Drug Metab Toxicol. 2017 Jul;13(7):767-782. doi: 10.1080/17425255.2017.1341489. Epub 2017 Jun 28.

Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

Author information

1
a Research & Biopharmacy, Institut de Recherches Internationales Servier , Suresnes , France.
2
b Pathology Sciences, Drug Safety and Metabolism , AstraZeneca R&D , Cambridge , UK.
3
c Preclinical Safety , AbbVie , North Chicago , USA.
4
d Non Clinical Development, Chemin du Foriest , UCB BioPharma SPRL , Braine L'Alleud , Belgium.
5
e Drug ADME Research, H. Lundbeck A/S , 9 Ottiliavej , Valby , Denmark.
6
f Non-Clinical Development, Merck KGaA , Darmstadt , Germany.
7
g In Vitro Biology , Orion Pharma , Espoo , Finland.
8
h Investigative Toxicology, Preclinical Safety , Sanofi R&D , Paris , France.
9
i Preclinical Development & Safety, Janssen (Pharmaceutical Companies of Johnson & Johnson) Turnhoutseweg 30 , Beerse , Belgium.
10
j Pathology Sciences, Drug Safety and Metabolism , AstraZeneca R&D , Cambridge , UK.
11
k Innovative Medicines and Early Clinical Development, Drug Safety and Metabolism, Discovery Safety , AstraZeneca R&D , Mölndal , Sweden.
12
l Pharmacokinetics Dynamics & Metabolism, Janssen (Pharmaceutical Companies of Johnson & Johnson) Turnhoutseweg 30 , Beerse , Belgium.
13
m Dept of Toxicology , Lilly Research Laboratories, Eli Lilly and Company , Indianapolis , Indiana , USA.
14
n Investigative Safety & Drug Metabolism , GlaxoSmithKline, David Jack Centre for Research and Development , Ware , Herts , Hertfordshire, UK.
15
o Institute of Translational Medicine , University of Liverpool , Liverpool , UK.

Abstract

The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

KEYWORDS:

DILI; HepG2; HepaRG; Human; IMI; cholestasis; cytotoxicity; drug development; drug discovery; endpoints; hepatobiliary; hepatocytes; immune system; liver; mitochondrial toxicity; test systems

PMID:
28604124
DOI:
10.1080/17425255.2017.1341489
[Indexed for MEDLINE]

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