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Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam, norflurazepam, and 4'‐chlorodiazepam (Ro5–4864)
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2019-02-05 , DOI: 10.1002/dta.2561 Bjoern Moosmann 1, 2 , Philippe Bisel 3 , Folker Westphal 4 , Maurice Wilde 2, 5 , Jürgen Kempf 2 , Verena Angerer 2 , Volker Auwärter 2
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2019-02-05 , DOI: 10.1002/dta.2561 Bjoern Moosmann 1, 2 , Philippe Bisel 3 , Folker Westphal 4 , Maurice Wilde 2, 5 , Jürgen Kempf 2 , Verena Angerer 2 , Volker Auwärter 2
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The number of newly appearing benzodiazepine derivatives on the new psychoactive substances (NPS) drug market has increased over the last couple of years totaling 23 ‘designer benzodiazepines’ monitored at the end of 2017 by the European Monitoring Centre for Drugs and Drug Addiction. In the present study, three benzodiazepines [flunitrazolam, norflurazepam, and 4′‐chlorodiazepam (Ro5–4864)] offered as ‘research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by gas chromatography−mass spectrometry (GC–MS), liquid chromatography−tandem mass spectrometry (LC MS/MS), liquid chromatography−quadrupole time of flight−mass spectrometry (LC−QTOF−MS) analysis and nuclear magnetic resonance (NMR) spectroscopy. The metabolic steps of flunitrazolam were monohydroxylation, dihydroxylation, and reduction of the nitro function. The detected in vitro phase I metabolites of norflurazepam were hydroxynorflurazepam and dihydroxynorflurazepam. 4’‐Chlorodiazepam biotransformation consisted of N‐dealkylation and hydroxylation. It has to be noted that 4′‐chlorodiazepam and its metabolites show almost identical LC–MS/MS fragmentation patterns to diclazepam and its metabolites (delorazepam, lormetazepam, and lorazepam), making a sufficient chromatographic separation inevitable. Sale of norflurazepam, the metabolite of the prescribed benzodiazepines flurazepam and fludiazepam, presents the risk of incorrect interpretation of analytical findings.
中文翻译：
设计师苯二氮卓类药物的表征和体外I期微粒体代谢：包括氟硝唑仑，去氟西epa和4'-氯二氮卓（Ro5-4864）的更新
在过去的几年中，新的精神活性物质（NPS）市场上新出现的苯二氮卓衍生物数量增加了，截至2017年底，欧洲药物和药物成瘾监测中心对23种``设计师苯二氮卓类药物''进行了监测。在本研究中，表征了在互联网上作为“研究化学品”提供的三种苯并二氮杂[氟尼唑兰，去氟西epa和4'-氯二氮卓（Ro5-4864）]，并对其主要体外作用进行了表征。与合并的人肝微粒体孵育后，初步鉴定出I期代谢物。对于所有化合物，通过气相色谱-质谱（GC-MS），液相色谱-串联质谱（LC MS / MS），液相色谱-四极杆飞行时间质谱（LC）确认了供应商声明的结构式-QTOF-MS）分析和核磁共振（NMR）光谱。氟硝唑拉姆的代谢步骤是单羟基化，二羟基化和硝基功能降低。所检测到的体外norflurazepam的I期代谢物hydroxynorflurazepam和dihydroxynorflurazepam。4'-氯地西epa的生物转化由N组成-脱烷基和羟基化。必须注意的是，4'-氯二氮杂及其代谢物的LC-MS / MS片段化模式与地西西am及其代谢物（地洛西p，洛美他西姆和劳拉西m）几乎相同，因此不可避免地需要进行足够的色谱分离。出售诺氟西epa（处方的苯二氮卓类氟拉西m和氟地西p的代谢物），存在对分析结果进行错误解释的风险。
更新日期：2019-02-05
中文翻译：
设计师苯二氮卓类药物的表征和体外I期微粒体代谢：包括氟硝唑仑，去氟西epa和4'-氯二氮卓（Ro5-4864）的更新
在过去的几年中，新的精神活性物质（NPS）市场上新出现的苯二氮卓衍生物数量增加了，截至2017年底，欧洲药物和药物成瘾监测中心对23种``设计师苯二氮卓类药物''进行了监测。在本研究中，表征了在互联网上作为“研究化学品”提供的三种苯并二氮杂[氟尼唑兰，去氟西epa和4'-氯二氮卓（Ro5-4864）]，并对其主要体外作用进行了表征。与合并的人肝微粒体孵育后，初步鉴定出I期代谢物。对于所有化合物，通过气相色谱-质谱（GC-MS），液相色谱-串联质谱（LC MS / MS），液相色谱-四极杆飞行时间质谱（LC）确认了供应商声明的结构式-QTOF-MS）分析和核磁共振（NMR）光谱。氟硝唑拉姆的代谢步骤是单羟基化，二羟基化和硝基功能降低。所检测到的体外norflurazepam的I期代谢物hydroxynorflurazepam和dihydroxynorflurazepam。4'-氯地西epa的生物转化由N组成-脱烷基和羟基化。必须注意的是，4'-氯二氮杂及其代谢物的LC-MS / MS片段化模式与地西西am及其代谢物（地洛西p，洛美他西姆和劳拉西m）几乎相同，因此不可避免地需要进行足够的色谱分离。出售诺氟西epa（处方的苯二氮卓类氟拉西m和氟地西p的代谢物），存在对分析结果进行错误解释的风险。
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