One of the major causes of small molecule mediated toxicity (organ toxicity, genotoxicity and carcinogenicity) is via metabolites formed by biotransformation, mainly in the liver.

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+ A significant proportion (∼78–86%) of drugs characterized by residual toxicity contain structural alerts and there is evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62–69% of these molecules. 

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+ Toxic metabolites often include reactive metabolite types such as quinones, nitroso-, acyl glucuronides, hydroxyl-amines and diols. 

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+ Parental structural alerts include epoxide, arene, 1-4 di hydroxy aromatic systems, primary amine and carboxylic acids.

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+ Drug toxicity and metabolism are often intrinsically linked and should not be viewed as separate or disparate data sets.

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Fully understanding the metabolic pathways and metabolites formed is essential to understanding drug toxicity mechanisms: ADME studies and in vitro studies for reaction phenotyping, MIST and DILI assessment are used to help provide these data.

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Dose is a crucial factor in drug toxicity and developing a molecule with a lower daily dose considerably de-risks away from severe toxicity.