Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.

Détails

ID Serval
serval:BIB_EBB6D8809FA2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.
Périodique
Toxicology In Vitro : An International Journal Published In Association With Bibra
Auteur(s)
Pomponio G., Zurich M.G. (co-premier), Schultz L., Weiss D.G., Romanelli L., Gramowski-Voss A., Di Consiglio E., Testai E.
ISSN
1879-3177 (Electronic)
ISSN-L
0887-2333
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
30
Numéro
1 Pt A
Pages
192-202
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The difficulty in mimicking nervous system complexity and cell-cell interactions as well as the lack of kinetics information has limited the use of in vitro neurotoxicity data. Here, we assessed the biokinetic profile as well as the neurotoxicity of Amiodarone after acute and repeated exposure in two advanced rodent brain cell culture models, consisting of both neurons and glial cells organized in 2 or 3 dimensions to mimic the brain histiotypic structure and function. A strategy was applied to evidence the abiotic processes possibly affecting Amiodarone in vitro bioavailability, showing its ability to adsorb to the plastic devices. At clinically relevant Amiodarone concentrations, known to induce neurotoxicity in some patients during therapeutic treatment, a complete uptake was observed in both models in 24 h, after single exposure. After repeated treatments, bioaccumulation was observed, especially in the 3D cell model, together with a greater alteration of neurotoxicity markers. After 14 days, Amiodarone major oxidative metabolite (mono-N-desethylamiodarone) was detected at limited levels, indicating the presence of active drug metabolism enzymes (i.e. cytochrome P450) in both models. The assessment of biokinetics provides useful information on the relevance of in vitro toxicity data and should be considered in the design of an Integrated Testing Strategy aimed to identify specific neurotoxic alerts, and to improve the neurotoxicity assay predictivity for human acute and repeated exposure.
Mots-clé
Amiodarone/administration & dosage, Amiodarone/pharmacokinetics, Animals, Anti-Arrhythmia Agents/administration & dosage, Anti-Arrhythmia Agents/pharmacokinetics, Brain/cytology, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian/cytology, Mice, Neurons/drug effects, Neurons/metabolism, Rats, Rats, Sprague-Dawley
Pubmed
Web of science
Création de la notice
02/02/2016 17:46
Dernière modification de la notice
17/01/2020 6:18
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