Pomponio Giuliana, Zurich Marie-Gabrielle, Schultz Luise, Weiss Dieter G, Romanelli Luca, Gramowski-Voss Alexandra, Di Consiglio Emma, Testai Emanuela
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.
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):192-202. doi: 10.1016/j.tiv.2015.01.012. Epub 2015 Feb 7.
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.
模拟神经系统复杂性和细胞间相互作用的困难以及动力学信息的缺乏限制了体外神经毒性数据的应用。在此，我们评估了胺碘酮在两种先进的啮齿动物脑细胞培养模型中急性和重复暴露后的生物动力学特征以及神经毒性，这两种模型由二维或三维组织的神经元和胶质细胞组成，以模拟脑组织型结构和功能。我们采用了一种策略来证明可能影响胺碘酮体外生物利用度的非生物过程，结果表明其能够吸附到塑料装置上。在治疗过程中已知会在一些患者中诱发神经毒性的临床相关胺碘酮浓度下，单次暴露后24小时内在两种模型中均观察到完全摄取。重复给药后，观察到生物蓄积，尤其是在三维细胞模型中，同时神经毒性标志物的改变更大。14天后，检测到胺碘酮的主要氧化代谢物（单-N-去乙基胺碘酮）水平有限，表明两种模型中均存在活性药物代谢酶（即细胞色素P450）。生物动力学评估为体外毒性数据的相关性提供了有用信息，在旨在识别特定神经毒性警报并提高人体急性和重复暴露神经毒性试验预测性的综合测试策略设计中应予以考虑。
