Chapter 13 - Investigating the link between drug metabolism and toxicity

Abstract

Metabolites can play a role in the pharmacology and toxicology of drugs. Thus, there is a need to characterize the potential bioactivity of key metabolites during the development of a new drug candidate. The need often arises when an unexpected pharmacology or toxicology finding occurs and questions of whether the finding is due to a metabolite need to be addressed. These types of questions are especially important if there is a toxicology finding that is species-specific. To best understand the role metabolism plays in an observed toxicity it is ideal to conduct a set of investigations to directly examining the issue, ideally these involve determination of: (1) the drug-related species present at the site of toxicity, (2) metabolic capacity at the site of toxicity and (3) methods to model the toxicity finding in in vitro and in vivo models. If successful, these investigative studies can define a mechanism of action for the observed toxicology which can be used to assess the risk for patients. This risk assessment can help determine whether the drug should continue or be discontinued in favor of a backup devoid of the issue.