Bioactivation of diclofenac in vitro and in vivo: correlation to electrochemical studies

Chemical Research in Toxicology
Kim G MadsenJørgen Olsen

Abstract

Diclofenac is widely used in the treatment of, for example, arthritis and muscle pain. The use of diclofenac has been associated with hepatotoxicity, which has been linked to the formation of reactive metabolites. Diclofenac can be metabolized to 4'-OH- and 5-OH-diclofenac, both of which are able to form quinone imines capable of reacting with, for example, GSH and nucleophilic groups in proteins. Electrochemistry has been shown to be a suitable tool for mimicking some types of oxidative drug metabolism and for studying the formation of reactive metabolites. In these studies, the electrochemical oxidation of diclofenac to a +16 Da metabolite was shown to be identical to a synthetic standard of 5-OH-diclofenac. Furthermore, two different experimental designs were investigated with respect to the electrochemical oxidation of 4'-OH- and 5-OH-diclofenac. In the first approach, the oxidized sample was collected in an aqueous solution of GSH, whereas in the other approach, GSH was added to the sample before the oxidation was performed. From these electrochemical oxidations, a range of GSH conjugates of 4'-OH- and 5-OH-diclofenac were observed and characterized by MS/MS. This allowed the development of sensitive LC-MS methods in order...Continue Reading

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Citations

Jun 14, 2013·Analytical and Bioanalytical Chemistry·Smriti Khera, Na Hu
Apr 8, 2010·Expert Opinion on Drug Metabolism & Toxicology·Anne Baumann, Uwe Karst
Dec 23, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Miina RuokolainenTapio Kotiaho
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Jun 10, 2021·Toxicology·Mary Alexandra SchleiffGrover Paul Miller
Oct 7, 2014·Chemical Research in Toxicology·Ugo Bussy, Mohammed Boujtita
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Dec 23, 2014·Analytical Chemistry·Floris T G van den BrinkAlbert van den Berg

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