In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography-high resolution mass spectrometry
In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography-high resolution mass spectrometry
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DOI：
10.1002/dta.2611
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发表时间：
2019-08-01
影响因子：
2.9
通讯作者：
Hudson, Simon
中科院分区：
文献类型：
--
作者：
Cutler, Charlotte;Hudson, Simon
新型合成阿片类药物（NSOs）是一类新型精神活性物质（NSOs），越来越受欢迎，并呈现出重大的公共卫生风险。这类药物包括强效镇痛药芬太尼的衍生物。环丙基芬太尼（CycP-F）于2017年8月首次向欧盟预警系统报告，随后仅在美国就与100多人死亡有关。有限的药理学，药代动力学或毒理学数据可用于许多新兴的国家统计局;然而，我们可以预期新的芬太尼类似物呈现有限的检测窗口，短起效，窄的治疗指数和非常高的效力的潜力。这些药物的代谢知识是必不可少的，以确定其检测的分析目标。因此，使用人肝微粒体孵育产生CycP-F的体外代谢产物。使用液相色谱-高分辨率精确质量分析（LC-HRAM）对形成的代谢产物进行解析。将鉴定的代谢物添加到我们用于后续筛选分析的准确质量筛选数据库中。在两个人血液病例样本中鉴定了CycP-F和代谢产物。在体外鉴定了11种代谢产物，主要代谢产物通过N-脱烷基化、单羟基化和N-氧化产生。对阳性病例样本的分析鉴定出4种体内代谢物，所有这些代谢物均在体外观察到。在体外和体内鉴别的主要代谢产物是N-脱烷基化的非代谢产物;在体内检测到另外两种单羟基化和一种二羟基化代谢产物。
Novel synthetic opioids (NSOs) are a class of novel psychoactive substances (NPS) that are growing in popularity and presenting a significant public health risk. Included in this class are derivatives of the highly potent analgesic, fentanyl. Cyclopropylfentanyl (CycP-F) was first reported to the EU Early Warning System in August 2017, and was subsequently linked to more than 100 deaths in the US alone. Limited pharmacological, pharmacokinetic or toxicological data is available for many emerging NSOs; however we can expect novel fentanyl analogues to present limited detection windows, short onset, narrow therapeutic indices and the potential for very high potency. Knowledge of the metabolism of these drugs is essential for the identification of analytical targets for their detection. Therefore in vitro metabolites of CycP-F were produced using human liver microsomal incubations. Metabolites formed were elucidated using liquid chromatography-high resolution accurate mass analysis (LC-HRAM). Identified metabolites were added to our accurate mass screening database for NPS which was utilised for subsequent screening analysis. CycP-F and metabolites were identified in two human blood case samples. Eleven metabolites were identified in vitro, with the major metabolites produced via N-dealkylation, monohydroxylation and N-oxidation. Analysis of the positive case samples identified four in vivo metabolites, all of which were observed in vitro. The major metabolite identified in vitro and in vivo was the N-dealkylated nor-metabolite; two further mono-hydroxylated and one dihydroxylated metabolite were detected in vivo.