Toxicokinetic studies and translational mechanistic modeling of New Psychoactive Substances using the Synthetic Cannabinoid Cumyl-5F-P7AICA.

拟议项目的一个主要目的是在已经建立的毒性动力学研究猪模型中全面表征合成大麻素cumyl-5F-P7AICA的毒性动力学特性。在吸入给药和制备收集的样本后，应建立血液/血清/呼出气体和脂肪组织的浓度-时间谱，并确定死亡时器官和组织中该物质的浓度。基于这些数据，大麻素的毒性动力学模型应该首先用异速缩放法建立。为了确保动物实验结果对人类情况的全面可转移性，应该使用已经研究过的进一步的大麻素（具有不同的核心结构）进行翻译方法或概念验证意义上的扩展建模。另外考虑到化合物的特定参数，如蛋白质结合和亲脂性，以及某些运输蛋白和降解酶，因此应该建立一个基于生理学的毒物动力学模型（PBTK），并通过异速尺度转移到人类身上。因此，需要将新建立的PBTK模型与JWH-210、RCS-4和THC等物质的前期工作模型进行对比，验证其有效性。另一个目的是测定不同环境条件下cumyl-5F-P7AICA的死后稳定性。为此，动物应在室温下露天或水中储存三天。24小时后，采集不同的器官和组织标本以及不同的体液样本进行分析。

A major aim of the proposed project is a comprehensive characterization of the toxicokinetic properties of the synthetic cannabinoid cumyl-5F-P7AICA in a pig model already established for toxicokinetic studies. Following inhalative administration and preparation of the collected samples, blood-/serum-/exhaled breath- and adipose tissue- concentration-time profiles should be established and the concentrations of the substance in the organs and tissues at the time of death should be determined. Based on these data, a toxicokinetic model for the cannabinoid should first be established using allometric scaling. In order to ensure a comprehensive transferability of the animal experimental findings to the human situation, an extended modeling in the sense of a translational approach or a proof-of-concept should be carried out using further cannabinoids (with different core structures) having already been investigated. With additional consideration of compound-specific parameters such as protein binding and lipophilicity as well as certain transport proteins and degrading enzymes, a physiology-based toxicokinetics model (PBTK) should thus be developed and transferred to humans by means of allometric scaling. In this way, the validity of the newly established PBTK modeling should be validated in comparison with the modeling developed in the preliminary work on the substances JWH-210, RCS-4 and THC.Another aim is the determination of the postmortem stability of cumyl-5F-P7AICA under different ambient conditions. For this purpose, the animals should be stored for three days at room temperature in the open air or in water. After 24 hours, different organ and tissue specimens as well as samples of different body fluids should be collected and analyzed.