For example, according to the FDA guidelines (FDA, 2005), if a metabolite represents more than 10% of parent compound in human (defined as a major metabolite), then it should be present in the animal species tested. This emphasises the importance of establishing major metabolites produced by different species using in vitro assays so that they can be covered in animal toxicity studies. This line of guidance is also recommended by the EU Commission

( EU, 2010). Following on from this, in order to evaluate click here non-clinical animal toxicology studies, the systemic exposure of the drug (quality, i.e. parent and/or metabolites, as well as quantity, i.e. extent and/or rates of formation) should be considered and compared between the test-species and humans (i.e. species-specific metabolism). This comparison is reasonable if the metabolic pathways are similar, however, in rare cases, if in vitro assays suggest that major metabolites produced in humans are not evident in animals, then further investigations into the toxicity of the metabolite are necessary. If it can be established that at least

one animal test-species produces major metabolite(s) observed in humans, it can be assumed that the metabolite’s contribution to the overall toxicity assessment has been taken into account. The use of in vitro assays, especially in early compound development, allows for selection much of compounds and, when possible, the most www.selleckchem.com/products/ABT-737.html suitable pre-clinical species, as well as flagging up compounds that may require additional toxicity studies to evaluate the contribution of the metabolites to the toxic effects ( Coecke et al., 2005b). Drug–drug interactions are most relevant to the pharmaceutical industry since often more than one drug is purposefully given at therapeutic doses to treat multiple symptoms/causes of illness (i.e. polypharmacy). Unfortunately, one drug may alter the pharmacokinetics of the co-therapy drug and result in either the loss of efficacy or increased toxicity of the latter. Metabolic inhibition of drugs can be

predicted using human liver microsomes whereas human hepatocytes are considered to be the “Gold Standard” for predicting metabolic induction (Table 1). Knowledge of potential drug–drug interactions is a vital part of the candidate (de)selection process as well as aiding in the design of clinical interaction trials. Significant progress has been made in the understanding of cellular-response networks, i.e. a network of pathways involving a complex biochemical interaction of genes, proteins, and small molecules that maintain normal cellular function. Advances in our knowledge of the pathways are allowing researchers to investigate how they are altered by environmental agents and ultimately lead to toxicity.