Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques
Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques
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DOI：
10.1007/s00216-014-8360-0
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发表时间：
2015-02-01
影响因子：
4.3
通讯作者：
Maurer, Hans H.
中科院分区：
文献类型：
--
作者：
Welter, Jessica;Kavanagh, Pierce;Maurer, Hans H.
5-APB（5-（2-aminopropyl）benzofuran）及其N-甲基衍生物5-MAPB（N-methyl-5-（2-aminopropyl）benzofuran）分别是苯丙胺和甲基苯丙胺的类似物，属于所谓的新型精神活性物质（NIPs）。它们被用作兴奋剂或具有欣快和兴奋作用的内毒素。由于这两种化合物在一些国家受到管制，因此应将其纳入临床和法医毒理学药物检测范围。因此，代谢研究是通过在单次给予高剂量的相应化合物后，采用固相萃取法处理大鼠尿液样本进行的，未进行酶结合物裂解或酶结合物裂解后进行。乙酰化后，通过GC-MS和/或LC-HR-MSn分离并鉴别I相代谢物，通过LC-HR-MSn分离并鉴别II相代谢物。5-APB的主要代谢产物为3-羧甲基-4-羟基苯丙胺，5-MAPB的主要代谢产物为5-APB（N-去甲基代谢产物）和3-羧甲基-4-羟基甲基苯丙胺。参与5-MAPB N-去甲基化的细胞色素P450（CYP）同工酶为CYP 1A 2、CYP 2B 6、CYP 2C 19和CYP 2D 6，根据动力学参数，CYP 2B 6负责总CYP依赖性清除的主要部分。采用作者的GCMS和LC-MSn标准尿液筛查方法，以相应的母体药物为主要目标，可以在大鼠尿液中确认摄入常用剂量的5-APB或5-MAPB。在摄入未知剂量的5-MAPB后的真实人尿样中，除了母体药物外，还可以检测到这两种代谢物。在6例临床病例中测定的5-MAPB血浆浓度范围为5 - 124 μ g/L，其N-去甲基代谢物5-APB的血浆浓度范围为1 - 38 μ g/L。
5-APB (5-(2-aminopropyl) benzofuran) and its N-methyl derivative 5-MAPB (N-methyl-5-(2-aminopropyl) benzofuran) are analogues of amphetamine and methamphetamine, respectively, and belong to the so-called novel psychoactive substances (NPS). They were consumed as stimulants or entactogens with euphoric and empathogenic effects. Being controlled in some countries, both compounds should be covered by drug testing in clinical and forensic toxicology. Therefore, metabolism studies have been performed by working up rat urine samples after a high single dose of the corresponding NPS with solid-phase extraction without and after enzymatic conjugates cleavage. The phase I metabolites were separated and identified after acetylation by GC-MS and/or LC-HR-MSn and the phase II metabolites by LC-HR-MSn. The main metabolite of 5-APB was 3-carboxymethyl-4-hydroxy amphetamine and the main metabolites of 5-MAPB were 5-APB (N-demethyl metabolite) and 3-carboxymethyl-4-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 5-MAPB N-demethylation were CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and according to the kinetic parameters, CYP2B6 was responsible for the main part of the total CYP-dependent clearance. An intake of a common users' dose of 5-APB or 5-MAPB could be confirmed in rat urine using the authors' GCMS and the LC-MSn standard urine screening approaches with the corresponding parent drugs as major target. In authentic human urine samples after ingestion of unknown doses of 5-MAPB, both metabolites could also be detected besides the parent drug. The plasma concentrations determined in six clinical cases ranged from 5 to 124 mu g/L for 5-MAPB and from 1 to 38 mu g/L for its N-demethyl metabolite 5-APB.