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

While drug toxicity (especially hepatotoxicity) is the most frequent reason cited forwithdrawal of an approved drug, no simple solution exists to adequately predict suchadverse events. simple cytotoxicity assays in hepg2 cells are relati vely insensitive to humanhepatotoxic drugs in a retrospective analysis of marketed pharmaceutical s, in comparison, apanel of pre-lethal mechanistic cellular assays hold the promise to deliver a more sensitiveapproach to detect endpoint-specific drug toxicities. the panel of assays co vered by thisreview includes steatosis, cholestasis, phospholipidosis, reactive intermediates, mitochondriamembrane function, oxidative stress, and drug interactions. in addition, the use of metabolicallycompetent cells or the introduction of major human hepatocytes in these in-vitro studies allowa more complete picture of potential drug side effect. since inter-individual therapeuticindex (ti) may differ from patient to patient, the rational use of one or more of these cellu larassay and targeted in-vivo exposure data may allow pharmaceutical scientists to select drugcandidates with a higher ti potential in the drug discovery phase.