The first-line antiepileptic drug carbamazepine: Reaction with biologically relevant free radicals

Inês L Martins, João Nunes, Catarina Charneira, Judit Morello, Sofia A Pereira, João P Telo, M Matilde Marques, Alexandra M M Antunes

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs by both adults and children. Despite its widespread use, CBZ is associated with central nervous system toxicity and severe hypersensitivity reactions, which raise concerns about its chronic use. While the precise mechanisms of CBZ-induced adverse events are still unclear, metabolic activation to the epoxide (CBZ-EP) has been thought to play a significant role. This work reports first-hand evidence that CBZ reacts readily with biologically relevant thiyl radicals with no need for bioactivation. Using liquid chromatography coupled with high resolution mass spectrometry, multiple products from direct reaction of CBZ with glutathione (GSH) and N-acetyl-L-cysteine (NAC) were unequivocally identified, including the same product obtained upon ring-opening of CBZ-EP. The product profile is complex and consistent with radical-mediated mechanisms. Importantly, side products and adducts compatible with this non-enzymatic pathway were identified in liver extracts from CBZ-treated Wistar rats. The reaction of CBZ with GSH and NAC is more extensive in the presence of oxygen. Taking into consideration that GSH conjugation is, in general, a detoxification pathway, these results suggest that under hyperoxia/oxidative stress conditions the bioavailability of the parent drug may be compromised. Additionally, this non-enzymatic process can be anticipated to play, at least in part, a role in the onset of CBZ-induced adverse effects due to the concomitant generation of reactive oxygen species. Therefore, the search for causal relationships between the formation of non-enzymatically-driven CBZ products and the occurrence of CBZ-induced adverse events in human patients merits further research, aiming the translation of basic mechanistic findings into a clinical context that may ultimately lead to a safer CBZ prescription.

Original languageEnglish
Pages (from-to)559-568
Number of pages10
JournalFree Radical Biology And Medicine
Volume129
Early online date17 Oct 2018
DOIs
Publication statusPublished - Dec 2018

Keywords

  • Carbamazepine
  • Covalent adducts
  • Glutathione conjugates
  • Mercapturates
  • Radical-based mechanism
  • Reactive oxygen species

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