可疑和非目标筛选工作流程可研究合成大麻素5Cl‐THJ‐018的体外和体内代谢,Drug Testing and Analysis

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可疑和非目标筛选工作流程可研究合成大麻素5Cl‐THJ‐018的体外和体内代谢
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2018-10-23 , DOI: 10.1002/dta.2508
Philippe Vervliet ₁ , Olivier Mortelé ₁ , Celine Gys ₁ , Maarten Degreef ₁ , Katrien Lanckmans ₂ , Kristof Maudens ₁ , Adrian Covaci ₁ , Alexander L.N. van Nuijs ₁ , Foon Yin Lai ₁

Affiliation

使用合成大麻素引起相似的效果Δ ⁹ -四氢大麻酚和长期（AB）的使用可导致健康危险和致命中毒。由于大多数研究的合成大麻素都经历了广泛的生物转化，因此尿液中几乎没有检测到母体化合物，这妨碍了法医研究。有关新型合成大麻素生物转化产物的信息有限，使得在各种生物基质中检测这些药物具有挑战性。这项研究旨在确定主要的体外5Cl‐THJ‐018的生物转化途径，并将这些发现与5Cl‐THJ‐018用户的真实尿液样本进行比较。将合成的大麻素与合并的人肝微粒体和细胞质一起孵育，以模拟I期和II期生物转化。通过液相色谱与四极杆飞行时间质谱（LC-QTOF-MS）结合对所得提取物进行分析。应用了三种不同的数据分析工作流程来识别生物转化产物。犯罪嫌疑人筛查工作流程使用了一个内部数据库，该数据库是根据文献数据和计算机生物转化预测建立的。两种非目标筛选工作流程使用了市售软件和开源软件进行质谱数据处理。总共23个体外确定了生物转化产物，其中羟基化，氧化脱氯和二氢二醇形成途径为主要的I相反应。另外，鉴定了五个葡糖醛酸化的和三个硫酸化的II相缀合物。体内主要途径是通过氧化脱氯作用，总共鉴定出5Cl‐THJ‐018六种代谢产物。使用互补的可疑和非靶标筛选工作流程成功地鉴定了体内和体外的生物转化产物。

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Suspect and non‐target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl‐THJ‐018

The use of synthetic cannabinoids causes similar effects as Δ⁹‐tetrahydrocannabinol and long‐term (ab)use can lead to health hazards and fatal intoxications. As most investigated synthetic cannabinoids undergo extensive biotransformation, almost no parent compound can be detected in urine, which hampers forensic investigations. Limited information about the biotransformation products of new synthetic cannabinoids makes the detection of these drugs in various biological matrices challenging. This study aimed to identify the main in vitro biotransformation pathways of 5Cl‐THJ‐018 and to compare these findings with an authentic urine sample of a 5Cl‐THJ‐018 user. The synthetic cannabinoid was incubated with pooled human liver microsomes and cytosol to simulate phase I and phase II biotransformations. Resulting extracts were analyzed with liquid chromatography coupled to quadrupole time‐of‐flight mass spectrometry (LC–QTOF–MS). Three different data analysis workflows were applied to identify biotransformation products. A suspect screening workflow used an in‐house database built from literature data and in silico biotransformation predictions. Two non‐target screening workflows used a commercially available software and an open‐source software for mass spectrometry data processing. A total of 23 in vitro biotransformation products were identified, with hydroxylation, oxidative dechlorination, and dihydrodiol formation pathways as the main phase I reactions. Additionally, five glucuronidated and three sulfated phase II conjugates were identified. The predominant in vivo pathway was through oxidative dechlorination and in total six metabolites of 5Cl‐THJ‐018 were identified. Biotransformation products both in vitro and in vivo were successfully identified using complementary suspect and non‐target screening workflows.

更新日期：2018-10-23

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