Metabolite elucidation of 2-fluoro-deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models,Drug Testing and Analysis

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Metabolite elucidation of 2-fluoro-deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2021-09-13 , DOI: 10.1002/dta.3162
Thomas Gicquel _{1,

2} , Romain Pelletier ₁ , Camille Richeval _{3,

4} , Alexandr Gish ₃ , Florian Hakim _{3,

4} , Pierre-Jean Ferron ₂ , Vadim Mesli ₅ , Delphine Allorge _{3,

4} , Isabelle Morel _{1,

2} , Jean-Michel Gaulier _{3,

4}

Affiliation

This work first aims to investigate metabolites of 2-fluoro-deschloroketamine (2F-DCK), a new arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances) using two in vitro experimental approaches, and to compare obtained results by means of molecular networking. Metabolites of 2F-DCK were investigated using both human liver microsomes (HLMs) and hepatic (HepaRG) cell line incubates using molecular networking approach: 2F-DCK pure substance was incubated with HLMs for up to 1 h at two concentrations (100 and 500 μM) and with HepaRG cells for two time periods (8 and 24 h) at one concentration (20 μM). In vitro obtained results were subsequently applied to a 2F-DCK-related fatality case. In vitro-produced metabolites were investigated using high-resolution accurate mass spectrometry using Orbitrap mass analyzer technology. Thirteen metabolites were in vitro produced and several metabolic pathways can be postulated. Seven additional metabolites were found in post-mortem samples (bile and urine) of the case, comprising three Phase II metabolites, which appear to be minor in vivo metabolites. HLMs and HepaRG cell models appear to be complementary and obtained data allowed the identification of several specific 2F-DCK metabolites in biological samples. In practical terms, observed metabolic ratios suggested that nor-2F-DCK (208.1137 m/z) and a hydrogenated metabolite (224.1443 m/z) could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of 2F-DCK use.

中文翻译：

使用分子网络跨三个互补的体外和体内模型阐明 2-氟代去氯氯胺酮 (2F-DCK) 的代谢物

这项工作首先旨在使用两种体外实验方法研究 2-氟脱氯氯胺酮 (2F-DCK) 的代谢物，这是一种新的芳基环己胺衍生物（一组可解离的氯胺酮基物质），并通过分子网络比较获得的结果. 使用人肝微粒体 (HLM) 和肝 (HepaRG) 细胞系孵育，使用分子网络方法研究 2F-DCK 的代谢物：2F-DCK 纯物质与 HLM 在两种浓度（100 和 500 μM）下孵育长达 1 小时) 和 HepaRG 细胞在一个浓度 (20 μM) 下两个时间段（8 和 24 小时）。随后将体外获得的结果应用于与 2F-DCK 相关的死亡病例。体外- 使用 Orbitrap 质量分析仪技术使用高分辨率精确质谱法研究产生的代谢物。体外产生了13 种代谢物，并且可以假设几种代谢途径。在该病例的尸检样本（胆汁和尿液）中发现了另外七种代谢物，包括三种 II 期代谢物，这些代谢物似乎是体内微量的代谢物。HLM 和 HepaRG 细胞模型似乎是互补的，并且获得的数据允许鉴定生物样品中的几种特定 2F-DCK 代谢物。实际上，观察到的代谢比表明 nor-2F-DCK (208.1137 m/z ) 和氢化代谢物 (224.1443 m/z) 可被提议作为可靠的代谢物记录在 HRMS 文库中，以改进对 2F-DCK 使用的检测。

更新日期：2021-09-13

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