In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid
In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid
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DOI：
10.2174/1570159x15666161108123419
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发表时间：
2017-01-01
影响因子：
5.3
通讯作者：
Huestis, Marilyn A.
中科院分区：
文献类型：
--
作者：
Carlier, Jeremy;Diao, Xingxing;Huestis, Marilyn A.
背景：新的精神活性物质(NPS)的代谢物图谱对于记录药物消费至关重要。N-(1-amino-3，3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1-Hindazole-3-carboxamide(ADB-FUBINACA)是一种新兴的合成大麻素，其毒理和代谢数据目前尚不清楚。用人肝微粒体孵育法评价其代谢稳定性。结果：在超联苯柱(Restek(R))上实现了代谢物的分离，获得了全扫描TOF-MS和信息相关的MS/MS数据。ADB-FUBINACA微球的半衰期为39.7分钟，预计肝清除量为9.0毫升/分钟/公斤，萃取率为0.5(中间清除剂)。共鉴定出23种代谢物。主要代谢途径是烷基和吲唑羟化、末端酰胺水解、随后的葡萄糖醛酸偶联物和脱氢。结论：我们推荐ADB-FUBINACA羟烷基、羟基脱氢烷基和羟基吲达唑代谢物作为ADB-FUBINACA的摄取标记物。N-脱烷基代谢物不是特定的ADB-FUBINACA代谢物，不应用作消费的明确标志。这是第一个ADB-FUBINACA体外代谢研究；需要进行体内实验，以便进行药代动力学和药效学研究或来自真实临床/法医病例的尿液来证实我们的结果。
Background: Metabolite profiling of novel psychoactive substances (NPS) is critical for documenting drug consumption. N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1-Hindazole-3-carboxamide (ADB-FUBINACA) is an emerging synthetic cannabinoid whose toxicological and metabolic data are currently unavailable.Methods: We aimed to determine optimal markers for identifying ADB-FUBINACA intake. Metabolic stability was evaluated with human liver microsome incubations. Metabolites were identified after 1 and 3 h incubation with pooled human hepatocytes, liquid chromatography-high resolution mass spectrometry in positive-ion mode (5600(+) TripleTOF (R), Sciex) and several data mining approaches (MetabolitePilot (TM), Sciex).Results: Metabolite separation was achieved on an Ultra Biphenyl column (Restek (R)); full-scan TOF-MS and information-dependent acquisition MS/MS data were acquired. ADB-FUBINACA microsomal half-life was 39.7 min, with a predicted hepatic clearance of 9.0 mL/min/kg and a 0.5 extraction ratio (intermediate-clearance drug). Twenty-three metabolites were identified. Major metabolic pathways were alkyl and indazole hydroxylation, terminal amide hydrolysis, subsequent glucuronide conjugations, and dehydrogenation.Conclusion: We recommend ADB-FUBINACA hydroxyalkyl, hydroxydehydroalkyl and hydroxylindazole metabolites as ADB-FUBINACA intake markers. N-dealkylated metabolites are not specific ADB-FUBINACA metabolites and should not be used as definitive markers of consumption. This is the first ADB-FUBINACA in vitro metabolism study; in vivo experiments enabling pharmacokinetic and pharmacodynamics studies or urine from authentic clinical/forensic cases are needed to confirm our results.