The Generation,Detection, and Effects of Reactive Drug Metabolites |
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Authors: | Andrew V Stachulski Thomas A Baillie B Kevin Park R Scott Obach Deepak K Dalvie Dominic P Williams Abhishek Srivastava Sophie L Regan Daniel J Antoine Christopher E P Goldring Alvin J L Chia Neil R Kitteringham Laura E Randle Hayley Callan J Luis Castrejon John Farrell Dean J Naisbitt Martin S Lennard |
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Institution: | 1. Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, , Liverpool, L69 7ZD UK;2. School of Pharmacy, University of Washington, , Seattle, Washington, 98195‐7631;3. Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, , Liverpool L69 3GE, UK;4. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, , Groton, Connecticut 06340;5. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, , La Jolla, California 94121;6. School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, , Liverpool L3 3AF, UK;7. Academic Unit of Medical Education, University of Sheffield, , Sheffield S10 2GJ, UK |
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Abstract: | The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein‐reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug–drug interactions that may ensue. One important class of protein‐reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates. |
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Keywords: | reactive drug metabolites covalent binding drug‐induced toxicity drug– drug interactions cytochromes P‐450 enzyme inhibition acyl glucuronides immunology drug design |
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