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New Technologies and Screening Strategies for Hepatotoxicity: Use of In Vitro ModelsDiscovery Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA Correspondence: Address correspondence to: Dr. Donna M. Dambach, Discovery Toxicology, Bristol-Myers Squibb, PRI, P.O. Box 4000, F14-03, Princeton, New Jersey 08543, USA; e-mail:donna.dambach{at}bms.com 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.
Key Words: Hepatotoxicity • in vitro cultures • CYP450 induction • biomarker • hepatocytes • screening Abbreviations: CYP450, cytochrome P450 • UDPGT, uridine phosphoglucuronosyltransferase • CMV, cytomegalovirus • IC50, 50% inhibitory concentration • MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-H-tetrazolium, inner salt • ATP, adenosine triphosphate • DMSO, dimethyl sulfoxide • µM, micromolar • ED50, 50% effective dose • SAR, structure activity relationship • ADME, absorption, distribution, metabolism, elimination • TZD, thiazolidinedione • PCA, principal component analysis • LC/LC/MS/MS, multidimensional packed capillary high performance liquid chromotography coupled tandem mass spectrometry • MIF, macrophage migration inhibitory factor • ELISA, enzyme linked immunosorbant assay • VOD, veno-occlusive disease
Toxicologic Pathology, Vol. 33, No. 1,
17-26 (2005) This article has been cited by other articles:
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