title: Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures.
abstract: 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.
authors: Mechanism of Toxicity Unit, Environment and Primary Prevention Department, Istituto Superiore di Sanità, Rome, Italy; Department of Physiology and Pharmacology "V. Erspamer", Università Sapienza, Rome, Italy.
authors: Giuliana
authors: G
authors: Pomponio
authors: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors: Marie-Gabrielle
authors: MG
authors: Zurich
authors: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, Rostock, Germany.
authors: Luise
authors: L
authors: Schultz
authors: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, Rostock, Germany.
authors: Dieter G
authors: DG
authors: Weiss
authors: Department of Physiology and Pharmacology "V. Erspamer", Università Sapienza, Rome, Italy.
authors: Luca
authors: L
authors: Romanelli
authors: Department of Animal Physiology, Institute of Biological Sciences, University of Rostock, Rostock, Germany.
authors: Alexandra
authors: A
authors: Gramowski-Voss
authors: Mechanism of Toxicity Unit, Environment and Primary Prevention Department, Istituto Superiore di Sanità, Rome, Italy. Electronic address: emma.diconsiglio@iss.it.
authors: Emma
authors: E
authors: Di Consiglio
authors: Mechanism of Toxicity Unit, Environment and Primary Prevention Department, Istituto Superiore di Sanità, Rome, Italy.
authors: Emanuela
authors: E
authors: Testai
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000889:Anti-Arrhythmia Agents; D000638:Amiodarone
keywords: 2D mouse brain cell culture; 3D rat brain cell culture; Amiodarone; Biokinetics; Neurotoxicity; Repeated exposure