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Application of Cell-Based Assay Systems for the Early Screening of Human Drug Hepatotoxicity in the Discovery Phase of Drug Development

Author(s): Jalal Pourahmad | Peter J O’Brien | Parivash Eftekhari

Journal: Iranian Journal of Pharmaceutical Research
ISSN 1735-0328

Volume: 4;
Issue: 4;
Start page: 191;
Date: 2005;
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Keywords: Cell-based system | Hepatotoxicity | Cytotoxicity | Mechanistic assay | Drug discovery

While drug toxicity (especially hepatotoxicity) is the most frequent reason cited for withdrawal of an approved drug, no simple solution exists to adequately predict such adverse events. Simple cytotoxicity assays in HepG2 cells are relatively insensitive to human hepatotoxic drugs in a retrospective analysis of marketed pharmaceuticals. In comparison, a panel of pre-lethal mechanistic cellular assays hold the promise to deliver a more sensitiveapproach to detect endpoint-specific drug toxicities. The panel of assays covered by this review includes steatosis, cholestasis, phospholipidosis, reactive intermediates, mitochondria membrane function, oxidative stress, and drug interactions. In addition, the use of metabolically competent cells or the introduction of major human hepatocytes in these in-vitro studies allow a more complete picture of potential drug side effect. Since inter-individual therapeutic index (TI) may differ from patient to patient, the rational use of one or more of these cellular assay and targeted in-vivo exposure data may allow pharmaceutical scientists to select drugcandidates with a higher TI potential in the drug discovery phase.

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