Reactive metabolites (RM) have been implicated in an array of adverse drug reactions (ADR), in particular idiosyncratic ADRs, with the liver being the most frequently affected organ. Historically, the focus in the pharmaceutical industry has been on minimizing the RM liability by designing away from structural motifs present in candidate drugs with the propensity to form RMs. While this approach of minimizing RM formation has been useful, it has been limited by the lack of quantitative endpoints and a holistic view of the RM hazard in conjunction with other potential toxicity hazards. Recently we developed a novel in vitro approach to assess the IADR risk associated with candidate drugs based on an integrated safety hazard assessment.1 This assessment was built around an estimated RM body burden based on covalent binding in human hepatocytes and the maximum daily dose, and then integrated into an overall assessment with in vitro measures of drug related hepatocyte toxicity, mitochondrial impairment and inhibition of hepatic transporters. Examples will be given illustrating the use of the approach in drug design and development, and its strengths and weaknesses. (1) Thompson, R. A.; Isin, E. M.; Li, Y.; Weidolf, L.; Page, K.; Wilson, I.; Swallow, S.; Middleton, B.; Stahl, S.; Foster, A. J.; Dolgos, H.; Weaver, R.; Kenna, J. G. (2012) In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs. Chem. Res. Toxicol. 25, 1616-1632.

Assessing the reactive metabolite hazard in candidate drugs

246th National Meeting (2013)

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