Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes
- Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340 (United States)
- Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340 (United States)
- Cyprotex US, Watertown, MA 02472 (United States)
- Computational Sciences, Pfizer Inc., Groton, CT 06340 (United States)
To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. - Highlights: • NSAIDS cause liver and GI toxicity. • Mitochondrial uncoupling contributes to NSAID liver toxicity. • ER stress is a mechanism that contributes to liver toxicity. • Zebrafish and cell based assays are complimentary.
- OSTI ID:
- 22285419
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 272, Issue 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants
Oxicam-derived non-steroidal anti-inflammatory drugs suppress 1-methyl-4-phenyl pyridinium-induced cell death via repression of endoplasmic reticulum stress response and mitochondrial dysfunction in SH-SY5Y cells