LC-high resolution-MS/MS for identification of 69 metabolites of the new psychoactive substance 1-(4-ethylphenyl-)-N-[(2-methoxyphenyl)methyl] propane-2-amine (4-EA-NBOMe) in rat urine and human liver S9 incubates and comparison of its screening power with further MS techniques
LC-high resolution-MS/MS for identification of 69 metabolites of the new psychoactive substance 1-(4-ethylphenyl-)-N-[(2-methoxyphenyl)methyl] propane-2-amine (4-EA-NBOMe) in rat urine and human liver S9 incubates and comparison of its screening power with further MS techniques
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DOI：
10.1007/s00216-017-0526-0
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发表时间：
2017
影响因子：
4.3
通讯作者：
A. Caspar;F. Westphal;M. Meyer;H. Maurer
中科院分区：
文献类型：
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作者：
A. Caspar;F. Westphal;M. Meyer;H. Maurer
4-EA-NBOMe（N-（2-甲氧基苄基）-4-乙基安非他明，1-（4-乙基苯基-）-N-[（2-甲氧基苯基）甲基]丙烷-2-胺）是一种源自安非他明的N-甲氧基苄基（NBOMe）类新精神活性物质（NGOMe），首次由德国海关当局缉获。与苯乙胺NBOMes相反，尚未发表关于药理学、毒理学或代谢特性的研究。本工作的目的是使用LC-HR-MS/MS鉴定大鼠尿液和合并的人S9组分（pS 9）孵育物中4-EA-NBOMe的I期和II期代谢物，比较两种模型中的代谢物形成，鉴定相关的单加氧酶，并使用GC-MS、LC-MSn、4-EA-NBOMe在大鼠体内主要通过乙基氧化为苯乙醛、苯甲酸或苯乙酸、羟基化、O-去甲基化以及葡萄糖醛酸化和硫酸化代谢。除氧化为苯甲酸外，所有主要代谢反应均可在pS 9孵育中确认。总共可鉴定出36种I相和33种II相代谢产物。单加氧酶活性筛选显示细胞色素P450（CYP）1A 2、CYP 2B 6和CYP 3A 4普遍参与。在低剂量给药后，所有SUSA仅通过其代谢产物检测到4-EA-NBOMe的摄入。两种LC-MS筛选的主要目标应该是苯乙酸衍生物、具有和不具有额外O-脱甲基作用的扁桃酸衍生物，以及对于GC-MS，缀合物裂解后的羟基代谢物。
4-EA-NBOMe (N-(2-methoxybenzyl)-4-ethylamphetamine, 1-(4-ethylphenyl-)-N-[(2-methoxyphenyl)methyl]propane-2-amine) is an amphetamine-derived new psychoactive substance (NPS) of theN-methoxybenzyl (NBOMe) group first seized by German custom authorities. In contrast to the phenethylamine NBOMes, studies on the pharmacological, toxicological, or metabolic properties are not yet published. The aims of the presented work were the use of LC-HR-MS/MS for identification of the phase I and II metabolites of 4-EA-NBOMe in rat urine and pooled human S9 fraction (pS9) incubations, to compare metabolite formation in both models, to identify involved monooxygenases, and to elucidate its detectability in standard urine screening approaches (SUSAs) using GC-MS, LC-MSn, and LC-HR-MS/MS. 4-EA-NBOMe was mainly metabolized by oxidation of the ethyl group to phenyl acetaldehyde, to benzoic acid, or to phenylacetic acid, by hydroxylation, and all combined withO-demethylation as well as by glucuronidation and sulfation of the main phase I metabolites in rats. With the exception of the oxidation to benzoic acid, all main metabolic reactions could be confirmed in the incubations with pS9. In total, 36 phase I and 33 phase II metabolites could be identified. Monooxygenase activity screenings revealed the general involvement of cytochrome-P450 (CYP) 1A2, CYP2B6, and CYP3A4. An intake of 4-EA-NBOMe was detectable only via its metabolites by all SUSAs after low-dose administration. The main targets for both LC-MS screenings should be the phenylacetic acid derivative, the mandelic acid derivative both with and without additionalO-demethylation, and, for GC-MS, the hydroxy metabolite after conjugate cleavage.