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Metabolic Activation-Role in Toxicity and Idiosyncratic Reactions

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Optimizing the “Drug-Like” Properties of Leads in Drug Discovery

Part of the book series: Biotechnology: Pharmaceutical Aspects ((PHARMASP,volume IV))

Abstract

Adverse drug reactions continue to pose a major impediment to drug development, and the clinical management of marketed products. These are typically divided into acute, dose dependent reactions (Type A), and reactions that may occur in only a small percentage of patients, where the frequency of occurrence in the population is not dependent on dose (Type B), although more complex classifications have also been proposed, (Park et al, 2000). According to a recent PhRMA review, the most frequently encountered toxicities in pre clinical drug development are hepatotoxicity and dermal reactions (Olson et al. 2000). Hepatotoxicity may take many forms (Ward and Daly 2001), so implying drug metabolism generally would be presumptive, but as the major organ responsible for the metabolism of drugs it seems clear that metabolism is important in many cases. Type A reactions generally may be mediated through parent compound or metabolites, and the role of chemically reactive metabolites has been well recognized (Hinson et al. 1994). Type B reactions, also referred to as idiosyncratic or hypersensitivity reactions, have been the subject of extensive reviews in recent years (Uetrecht 2000, Ju and Uetrecht, 2002). These are generally believed to be immune mediated, and are not predictable from pre clinical animal studies, thus they may not be identified until late clinical stages, or post marketing. Type B reactions have been reported to constitute 25% of all clinical adverse events (Lazarou et al, 1998). While direct T cell stimulation has been proposed as a possible mechanism (Zanni et al. 1998), bioactivation to reactive metabolites that covalently bind to proteins is still believed to be a key event in the origin of most Type B reactions, and is the basis of the Hapten hypothesis (Uetrecht 2003).

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  1. Dept of Drug Metabolism Metabolic and Viral Center for Excellence in Drug Discovery, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709

    John S. Walsh

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  1. University of Kansas, Lawrence, KS, 66045, USA

    Ronald T. Borchardt

  2. Wyeth Research, Monmouth Junction, NJ, 08852, USA

    Edward H. Kerns

  3. Pfizer, Inc., Kalamazoo, MI, 49007, USA

    Michael J. Hageman

  4. University of North Carolina, Chapel Hill, NC, 27599, USA

    Dhiren R. Thakker

  5. Eli Lilly Research Laboratory, Greenfield, IN, 46285, USA

    James L. Stevens

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Walsh, J.S. (2006). Metabolic Activation-Role in Toxicity and Idiosyncratic Reactions. In: Borchardt, R.T., Kerns, E.H., Hageman, M.J., Thakker, D.R., Stevens, J.L. (eds) Optimizing the “Drug-Like” Properties of Leads in Drug Discovery. Biotechnology: Pharmaceutical Aspects, vol IV. Springer, New York, NY. https://doi.org/10.1007/978-0-387-44961-6_3

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