Abstract
We have developed a metabolomics data base (MetaMap®Tox) containing the plasma metabolome changes induced by more than 500 data rich chemicals, agrochemicals and active pharmaceutical ingredients derived from 28 day repeated dose toxicity studies in Wistar rats. Throughout its routine application within BASF’s experimental toxicology department, we have shown the robustness, reproducibility and predictive performance of this technique in combination with our reference data base MetaMap®Tox.Based on metabolite profiling after 7, 14 and 28 days of treatment with the test substances, more than 110 characteristic patterns of metabolite changes have been validated that are specific for a given toxicological effect. These patterns a based on common metabolome effects of groups of reference compounds, which share a common toxicological effect, pathway or mechanism. These pathways comprise different mechanisms of toxicity in e.g., liver, kidney, thyroid, adrenals, testis, the endocrine system and many more target organs. Although the patterns have been developed for the application in 28 day rat studies, the majority of them can also be used for a plasma metabolome analysis in shorter studies, such as exploratory 14 day rat studies. Metabolic profiling has capabilities in detecting signals in preclinical studies that might portend clinical DILI. Such directed non-clinical studies can help to minimize the risk of medication in clinical studies. Examples for patterns as well as case studies on DILI will be shown to display the value of the metabolome analysis in the context of targeted preclinical testing.
