New technologies and screening strategies for hepatotoxicity: use of in vitro models.
Hepatotoxicity remains a significant cause for drug failures during clinical trials. This is due, in part, to the idiosyncratic nature of toxicity in humans and inherent physiological differences between humans and preclinical species leading to limited correct prediction of adverse responses in humans. To address this issue, robust screening assays are being developed, which have heightened predictive capacity for human hepatotoxicity, and may be utilized throughout the discovery and development phases in conjunction with traditional in vivo methods, for decision making during drug selection and risk assessment. This manuscript describes an example application of in vitro-based strategies using human hepatocyte cultures in lead optimization screening in conjunction with ADME profiling, for evaluation of compound-associated CYP450 induction potential, and the identification of potentially useful biomarkers as predictors of hepatotoxicity for use in vitro, and in preclinical species and humans.
Dambach
Donna M
DM
Discovery Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. donna.dambach@bms.com
Andrews
Barbara A
BA
Moulin
Frederic
F
D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D015195:Drug Design; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans
D015415:Biomarkers; D003577:Cytochrome P-450 Enzyme System