Comparisons betweenin vitrowhole cell imaging andin vivozebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development

Autor:	Natalie Mesens, Adrian Hill, Jinghai James Xu, Michael D. Aleo, Margino Steemans
Rok vydání:	2012
Předmět:	Drug-Related Side Effects and Adverse Reactions Pharmacology Bioinformatics In vivo medicine Animals Humans Pharmacology (medical) General Pharmacology Toxicology and Pharmaceutics Zebrafish Liver injury biology business.industry Reproducibility of Results medicine.disease biology.organism_classification In vitro Liver Drug development Drug Design High-content screening Hepg2 cells Models Animal Chemical and Drug Induced Liver Injury Whole cell business
Zdroj:	Drug Metabolism Reviews. 44:127-140
ISSN:	1097-9883 0360-2532
DOI:	10.3109/03602532.2011.645578
Popis:	Drug-induced liver injury (DILI) is a major cause of attrition during both the early and later stages of the drug development and marketing process. Reducing or eliminating drug-induced severe liver injury, especially those that lead to liver transplants or death, would be tremendously beneficial for patients. Therefore, developing new pharmaceuticals that have the highest margins and attributes of hepatic safety would be a great accomplishment. Given the current low productivity of pharmaceutical companies and the high costs of bringing new medicines to market, any early screening assay(s) to identify and eliminate pharmaceuticals with the potential to cause severe liver injury in humans would be of economic value as well. The present review discusses the background, proof-of-concept, and validation studies associated with high-content screening (HCS) by two major pharmaceutical companies (Pfizer Inc and Jansen Pharmaceutical Companies of Johnson & Johnson) for detecting compounds with the potential to cause human DILI. These HCS assays use fluorescent-based markers of cell injury in either human hepatocytes or HepG2 cells. In collaboration with Evotec, an independent contract lab, these two companies also independently evaluated larval zebrafish as an early-stage in vivo screen for hepatotoxicity in independently conducted, blinded assessments. Details about this model species, the need for bioanalysis, and, specifically, the outcome of the phenotypic-based zebrafish screens are presented. Comparing outcomes in zebrafish against both HCS assays suggests an enhanced detection for hepatotoxicants of most DILI concern when used in combination with each other, based on the U.S. Food and Drug Administration DILI classification list.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a3e99ee1b84380251d1e70d9cfed44c https://doi.org/10.3109/03602532.2011.645578 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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