2011
DOI: 10.1038/nrd3408
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Managing the challenge of chemically reactive metabolites in drug development

Abstract: The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At e… Show more

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Cited by 399 publications
(372 citation statements)
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“…HepaRG cells have been used in a variety of studies, including those involving liver toxicity [49,50], hepatitis viruses infection [51], human hepatic diseases and differentiation. The currently used differentiation procedure takes 4 weeks in DMSO-treated medium.…”
Section: Discussionmentioning
confidence: 99%
“…HepaRG cells have been used in a variety of studies, including those involving liver toxicity [49,50], hepatitis viruses infection [51], human hepatic diseases and differentiation. The currently used differentiation procedure takes 4 weeks in DMSO-treated medium.…”
Section: Discussionmentioning
confidence: 99%
“…Skin is the tissue most commonly targeted by immune cells; however, other organs, including the liver, can be damaged either in isolation or as part of a generalized hypersensitivity syndrome. 1 T-lymphocytes are believed to cause drug-induced skin injury through the action of cytokines and cytolytic molecules. To stimulate a T-cell response the drug must bind to human leukocyte antigen (HLA) and in some way crosslink specific T-cell receptors.…”
mentioning
confidence: 99%
“…When the dose of reactive metabolites exceeds the capacity of this defence system to replenish glutathione through new synthesis, glutathione depletion occurs. For a variety of toxic compounds, it has been found that the depletion of glutathione precedes the covalent binding of chemically reactive metabolites to cellular macromolecules, oxidative stress and, ultimately, organelle injury with the potential for liver failure and death (Park et al 2011). A more complete understanding of the events that lead to hepatic glutathione depletion might therefore highlight new and sensitive biomarkers and provide insights into key steps in glutathione production, thereby leading to improvements in risk assessment for new, and existing, drugs and xenobiotics.…”
Section: Introductionmentioning
confidence: 99%