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首页> 外文期刊>Journal of mass spectrometry: JMS >Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS
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Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS

机译：使用GC-MS和LC-高分辨率MS研究大鼠和人尿液和人肝微粒体中α-吡咯烷苯酮设计药物亚甲二氧基-吡咯烷酮（MDPV）的代谢及其在尿液中的可检测性

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摘要

Since the late 1990s, many derivatives of the α-pyrrolidinophenone (PPP) drug class appeared on the drugs of abuse market. The latest compound was described in 2009 to be a classic PPP carrying a methylenedioxy moiety remembering the classic entactogens (ecstasy). Besides Germany, 3,4-methylene-dioxypyrovalerone (MDPV) has appeared in many countries in Europe and Asia, indicating its worldwide importance for forensic and clinical toxicology. The aim of the presented work was to identify the phase I and II metabolites of MDPV and the human cytochrome-P450 (CYP) isoenzymes responsible for its main metabolic step(s). Finally, the detectability of MDPV in urine by the authors' systematic toxicological analysis (STA) should be studied. The urine samples were extracted after and without enzymatic cleavage of conjugates. The metabolites were separated and identified after work-up by GC-MS and liquid chromatography (LC)-high-resolution MS (LC-HR-MS). The studies revealed the following phase I main metabolic steps in rat and human: demethylenation followed by methylation, aromatic and side chain hydroxylation and oxidation of the pyrrolidine ring to the corresponding lactam as well as ring opening to the corresponding carboxylic acid. Using LC-HR-MS, most metabolite structures postulated according to GC-MS fragmentation could be confirmed and the phase II metabolites were identified. Finally, the formation of the initial metabolite demethylenyl-MDPV could be confirmed using incubation of human liver microsomes. Using recombinant human CYPs, CYP 2C19, CYP 2D6 and CYP 1A2 were found to catalyze this initial step. Finally, the STA allowed the detection of MDPV metabolites in the human urine samples.
机译：自1990年代后期以来，滥用药物市场上出现了许多α-吡咯烷二酮（PPP）衍生物。最新的化合物在2009年被描述为带有经典的actactogens（摇头丸）的带有亚甲二氧基部分的经典PPP。除德国外，3,4-亚甲基-二氧基吡咯烷酮（MDPV）已在欧洲和亚洲的许多国家/地区出现，表明其在法医和临床毒理学方面的全球重要性。提出的工作的目的是鉴定MDPV的I和II期代谢产物以及负责其主要代谢步骤的人细胞色素P450（CYP）同工酶。最后，应研究作者通过系统的毒理学分析（STA）检测尿液中MDPV的能力。在缀合物酶切和未酶切后提取尿液样品。通过GC-MS和液相色谱（LC）-高分辨率MS（LC-HR-MS）处理后，分离并鉴定了代谢物。研究表明，在大鼠和人类中，I期主要代谢步骤如下：先进行脱甲基化，然后进行甲基化，芳族和侧链羟基化，然后将吡咯烷环氧化成相应的内酰胺，以及将开环转化为相应的羧酸。使用LC-HR-MS，可以确认大多数根据GC-MS碎片推测的代谢物结构，并鉴定了II期代谢物。最后，可以通过孵育人肝微粒体来确认初始代谢物脱亚甲基-MDPV的形成。使用重组人CYP，发现CYP 2C19，CYP 2D6和CYP 1A2可以催化这一初始步骤。最后，STA允许检测人尿液样品中的MDPV代谢产物。

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