Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 192, Issue 1-2, Pages 46-55Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2010.09.003
Keywords
Drug; Reactive metabolites; Cytochrome P450; ADRs; Toxicity; Glutathione; Covalent binding
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Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) as opposed to the parent molecules from which they are derived are thought to be responsible for the pathogenesis of some IADRs. procedures (RM trapping/covalent binding) are being incorporated into the discovery screening funnel early-on to assess the risk of RM formation. Utility of the methodology in structure-toxicity relationships and scope in abrogating RM formation at the lead optimization stage are discussed in this article. Interpretation of the output from RM assessment assays, however, is confounded by the fact that many successfully marketed drugs are false positives. Therefore, caution must be exercised in deprioritizing a compound based on a positive result, so that the development of a useful and potentially profitable compound won't be unnecessarily halted. Risk mitigation strategies (e.g., competing detoxication pathways, low daily dose, etc.) when selecting RM positives for clinical development are also reviewed. (C) 2010 Published by Elsevier Ireland Ltd.
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