2020
DOI: 10.1124/dmd.120.000254
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Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Abstract: Meclofenamate is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain yet poses a rare risk of hepatotoxicity through an unknown mechanism. NSAID bioactivation is a common molecular initiating event for hepatotoxicity. Thus, we hypothesized a similar mechanism for meclofenamate and leveraged computational and experimental approaches to identify and characterize its bioactivation. Analyses employing our XenoNet model indicated possible pathways to meclofenamate bioactivation int… Show more

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Cited by 10 publications
(9 citation statements)
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“…It is thought that this toxicity is initiated as a result of cytochrome P450 bioactivation that forms covalent adducts to hepatic proteins and glutathione (GSH) (Galati et al, 2002). Here the investigators (Schleiff et al, 2021) used computational and experimental approaches to analyze possible key reactive metabolite formations.…”
Section: Referencesmentioning
confidence: 99%
“…It is thought that this toxicity is initiated as a result of cytochrome P450 bioactivation that forms covalent adducts to hepatic proteins and glutathione (GSH) (Galati et al, 2002). Here the investigators (Schleiff et al, 2021) used computational and experimental approaches to analyze possible key reactive metabolite formations.…”
Section: Referencesmentioning
confidence: 99%
“…It is thought that this toxicity is initiated as a result of cytochrome P450 bioactivation that forms covalent adducts to hepatic proteins and glutathione (GSH) (Galati et al 2002). Here the investigators (Schleiff et al 2021) used computational and experimental approaches to analyze possible key reactive metabolite formations. Through computational methods, 19 possible reactive metabolites highlighted possible reactions including metabolites resulting from monooxidation, dioxidation and/or oxidation followed by the resulting dechlorination.…”
Section: Commentarymentioning
confidence: 99%
“…These computational analyses are more accessible than experiments and provide an opportunity to readily explore potential relationships between molecular structure and bioactivation that lead to testable hypotheses. In practice, we couple high throughput computational studies with experimental efforts to validate predicted relationships and reveal model shortcomings for further refinement into practical tools, as shown through our work on terbinafine [16], thiazoles [17,18], and diphenylamine nonsteroidal anti-inflammatory drugs [19]. In this study, we applied our novel computational and experimental strategy to reveal the potential bioactivation liabilities of bromodomain and extra-terminal (BET) inhibitors.…”
Section: Introductionmentioning
confidence: 99%
“…Herein, we carried out a novel coupled modeling strategy to predict bioactivation pathways involving isoxazoles and validated them experimentally for selected BET inhibitors that are currently in development. The identification of possible bioactivation pathways for isoxazoles involved coupling deep neural models for quinone species formation, metabolite structures, and then biomolecule reactivity, as described previously [19]. Next, we assessed the capacity of our quinone model to identify potential electrophilic metabolites generated for isoxazole-containing molecules in the Accelrys Metabolite Database (AMD).…”
Section: Introductionmentioning
confidence: 99%
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