title: Alternatives in pharmaceutical toxicology: global and focussed approaches--two case studies.
abstract: Safety testing of potential drugs has been and will continue to be a challenging task for the toxicologist in the pharmaceutical industry. We present two examples for the use of target-specific cell models to detect and assess species-specific toxicity. In the first example, adrenal models based on primary cells as well as a permanent human adrenal cell line were used. Both cell systems enabled a good prediction of adrenal effects in rodents, non-rodents and humans. The second example made use of primary hepatocytes. In this project, a potential drug candidate showed unexpected toxicity in vitro as well as species-specific cytochrome P450 (CYP) induction in vivo. We therefore analysed CYP induction and gene expression signatures in rat and human hepatocytes as well as in samples from in vivo animal toxicity studies. By this approach, the rat hepatocyte model correctly predicted the effects observed in rats and the in vitro/in vivo comparison enabled a solid extrapolation of consequences in humans. These examples demonstrate that an intelligent testing strategy, using alternative methods, can enable a meaningful safety assessment for humans by adding a ''tailor-made'' range of technologies to ''classic'' toxicological methods.
authors.affiliation: Molecular Toxicology, Institute of Toxicology, Merck KGaA, Darmstadt, Germany. stefan.o.mueller@merck.de
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Mueller
authors.forename: Gregor
authors.initials: G
authors.lastname: Tuschl
authors.forename: Margret
authors.initials: M
authors.lastname: Kling
mesh_terms: D000311:Adrenal Glands / Q000166:cytology; D000826:Animal Testing Alternatives; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D051381:Rats; D012449:Safety; D014116:Toxicology / Q000379:methods*
chemical_list: D003577:Cytochrome P-450 Enzyme System