基于超高效液相色谱-Q Exactive质谱的合成大麻素5F-ADB、5F-MDMB-PICA和ADB-FUBINACA体外代谢研究  

Metabolic profiling of synthetic cannabinoids 5F-ADB, 5F-MDMB-PICA and ADB-FUBINACA in vitro using ultra performance liquid chromatography-Q Exactive mass spectrometry

作　　者：柯星 周善慧 卓晓聪[2] 詹国正 何丹丹 范一雷 宗兴森[1] KE Xing;ZHOU Shan-hui;ZHUO Xiao-cong;ZHAN Guo-zheng;HE Dan-dan;FAN Yi-lei;Zong Xing-sen(Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province,Zhejiang Police College,Hangzhou 310051,China;Xiaoshan Branch of Hangzhou Public Security Bureau,Hangzhou 311200,China;School of Chemical Engineering,Zhejiang University of Technology,Hangzhou 310012,China)

机构地区：[1]浙江警察学院浙江省毒品防控技术研究重点实验室,杭州310051 [2]杭州市公安局萧山分局,杭州311200 [3]浙江工业大学化工学院,杭州310012

出　　处：《药物分析杂志》2023年第1期113-125,共13页Chinese Journal of Pharmaceutical Analysis

基　　金：浙江省基础公益研究计划项目(LGC_(21)B050001);国家重点研发计划项目(2018YFC0807401);浙江省毒品防控技术研究重点实验室开放课题(2020010)。

摘　　要：目的:探究合成大麻素3,3-二甲基-2-[1-(5-氟戊基)-1H-吲唑-3-甲酰氨基]丁酸甲酯(5F-ADB)、3-二甲基-2-[1-(5-氟戊基)-1H-吲哚-3-甲酰氨基]丁酸甲酯(5F-MDMB-PICA)、N-[1-(氨基羰基)-2,2-二甲基丙基]-1-[(4-氟苯基)甲基]-1H-吲唑-3-甲酰胺(ADB-FUBINACA)的体外代谢产物及其代谢途径。方法:建立大鼠肝微粒体孵育模型,在37℃金属浴孵育60 min后离心,处理后样本采用超高效液相色谱-Q Exactive质谱ESI^(+)模式检测,使用0.1%甲酸水溶液和0.1%甲酸乙腈混合溶液作为流动相,Waters UPLC HSS T3作为色谱柱,运用Full MS/dd-MS^(2)扫描模式对合成大麻素母药及其代谢产物进行检测。结果:经鼠肝微粒体体外孵育实验,检测到5F-ADB脱氟加羟基化、脱氟氧化为戊酸、羟基化、酯水解、酯水解加脱氟羟基化、酯水解加脱氟氧化成羧酸等代谢途径产生的6种代谢产物,其分子式分别为C_(20)H_(29)N_(3)O_(4)、C_(20)H_(27)N_(3)O_(5)、C_(20)H_(28)FN_(3)O_(4)、C_(19)H_(26)FN_(3)O_(3)、C_(19)H_(27)N_(3)O_(4)、C_(20)H_(27)N_(3)O_(5);5F-MDMB-PICA脱氟加羟基化、脱氟氧化为戊酸、羟基化、酯水解、酯水解加脱氟羟基化等代谢途径产生的6种代谢产物,其分子式分别为C_(21)H_(30)N_(2)O_(4)、C_(21)H_(28)N_(2)O_(5)、C_(21)H_(29)FN_(2)O_(4)、C_(20)H_(27)FN_(2)O_(3)、C_(20)H_(28)N_(2)O_(4)和C_(20)H_(27)FN_(2)O_(4);ADB-FUBINACA通过脱氟加羟基化、脱氟氧化为戊酸、羟基化、酯水解和酯水解加脱氟羟基化等代谢途径产生的5种体外代谢产物,其分子式分别为C_(21)H_(21)FN_(4)O_(2)、C_(21)H_(22)FN_(3)O_(3)、C_(21)H_(20)FN_(3)O_(3)、C_(21)H_(23)FN_(4)O_(3)和C_(21)H_(22)FN_(3)O_(4)。结论:本研究解析了3种合成大麻素体外代谢途径及其代谢产物,为此类合成大麻素的体内检测提供科学依据。Objective: To explore the metabolites and metabolic pathways of synthetic cannabinoids methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3, 3-dimethylbutanoate(5F-ADB), methyl 2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3, 3-dimethylbutanoate(5F-MDMB-PICA), and N-(1-amino-3, 3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide(ADB-FUBINACA) in vitro. Methods: The incubation model of rat liver microsome was established. The liver microsome was incubated in 37 ℃ metal bath for 60 min and centrifuged. The processed sample was detected by ultra high performance liquid chromatography-Q Executive mass spectrometry under ESI^(+)mode. The liquid phase mobile phase was 0.1% formic acid-water and 0.1% formic acid-acetonitrile. The separation chromatographic column was Waters UPLC HSS T3. Full MS/dd-MS^(2) scanning mode was used to detect the synthetic cannabinoid and its metabolites. Results: In vitro incubation experiment of rat liver microsomes, six metabolites were detected from the metabolic pathways of 5F-ADB, including defluorination plus hydroxylation, defluorination oxition to valeric acid, hydroxylation, ester hydrolysis, ester hydrolysis plus defluorination hydroxylation, and ester hydrolysis plus defluorination oxition to carboxylic acid, and their molecular formula were C_(20)H_(29)N_(3)O_(4), C_(20)H_(27)N_(3)O_(5), C_(20)H_(28)FN_(3)O_(4), C_(19)H_(26)FN_(3)O_(3), C_(19)H_(27)N_(3)O_(4), and C_(20)H_(27)N_(3)O_(5), respectively. Six metabolites were detected by metabolic pathways of 5F-MDMB-PICA, including defluorination plus hydroxylation, defluorination to valeric acid, hydroxylation, ester hydrolysis, and ester hydrolysis and defluorination, and their molecular formula were C_(21)H_(30)N_(2)O_(4), C_(21)H_(28)N_(2)O_(5), C_(21)H_(29)FN_(2)O_(4), C_(20)H_(27)FN_(2)O_(3), C_(20)H_(28)N_(2)O_(4)and C_(20)H_(27)FN_(2)O_(4)respectively. Five metabolites were detected by metabolic pathways of ADB-FUBINACA, including defluorination plus hydroxylation, defluorination oxition, hydroxy

关 键 词：合成大麻素 新精神活性物质 鼠肝微粒体 液质联用 代谢产物 生物标记物 代谢途径 

分 类 号：R917[医药卫生—药物分析学]