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-MS2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C20H29N3O4、C20H27N3O5、C20H28FN3O4、C19H26FN3O3、C19H27N3O4、C20H27N3O5;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C21H30N2O4、C21H28N2O5、C21H29FN2O4、C20H27FN2O3、C20H28N2O4和C20H27FN2O4;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C21H21FN4O2、C21H22FN3O3、C21H20FN3O3、C21H23FN4O3和C21H22FN3O4。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。
柯星, 周善慧, 卓晓聪, 詹国正, 何丹丹, 范一雷, 宗兴森
. 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*[J]. 药物分析杂志, 2023
, 43(1)
: 113
-125
.
DOI: 10.16155/j.0254-1793.2023.01.14
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-MS2 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 C20H29N3O4, C20H27N3O5, C20H28FN3O4, C19H26FN3O3, C19H27N3O4, and C20H27N3O5, 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 C21H30N2O4, C21H28N2O5, C21H29FN2O4, C20H27FN2O3, C20H28N2O4 and C20H27FN2O4 respectively. Five metabolites were detected by metabolic pathways of ADB-FUBINACA, including defluorination plus hydroxylation, defluorination oxition, hydroxylation, ester hydrolysis and ester hydrolysis plus defluorination hydroxylation, and their molecular formula were C21H21FN4O2, C21H22FN3O3, C21H20FN3O3, C21H23FN4O3, and C21H22FN3O4, respectively. Conclusion: This study analyzes the metabolites and metabolic pathways of synthetic cannabinoids in vitro, and thus provides a scientific basis for the detection of synthetic cannabinoids in vivo.
[1] ELSOHLY MA, GUL W, WANAS AS, et al. Synthetic cannabinoids: analysis and metabolites[J].Life Sci, 2014, 97(1):78
[2] MILLS B, YEPES A, NUGENT K. Synthetic cannabinoids[J].Am J Med Sci, 2015, 350(1):59
[3] POTTS AJ, CANO C, THOMAS HL, et al. Synthetic cannabinoid receptor agonists: classification and nomenclature[J].Clin Toxic, 2019, 58(2):1
[4] 杜宇, 王优美, 狄斌, 等. 合成大麻素结构特征分类及其命名问题分析[J].刑事技术, 2022, 47(3):1226
DU Y, WANG YM, DI B, et al. Confusion and inadequacy with nomenclature of synthetic cannabinoids[J].Forensic Sci Technol, 2022, 47(3):1226
[5] SHIYANG Q, GUOBIN X, JUANNA W, et al. Metabolic profiles of 5F-MDMB-PICA in human urine, serum and hair samples using LC-Q Exactive HF-MS[J].J Anal Toxic, 2021, 46(4):408
[6] KAVANAGH P, GRIGORYEV A, KRUPINA N. Detection of metabolites of two synthetic cannabimimetics, MDMB-FUBINACA and ADB-FUBINACA, in authentic human urine specimens by accurate mass LC-MS: a comparison of intersecting metabolic patterns[J].Forensic Toxic, 2017, 35(2):284
[7] YETER O, OZTURK YE. Metabolic profiling of synthetic cannabinoid 5F-ADB by human liver microsome incubations and urine samples using high-resolution mass spectrometry[J].Drug Test Anal, 2019, 11(6):847
[8] 施妍, 周莉英, 沈保华, 等. 毛发中7种常见合成大麻素类新精神活性物质的分析及应用[J].法医学杂志, 2021, 37(4):479
SHI Y, ZHOU LY, SHEN BH, et al. Analysis and application of seven common new psychoactive substances of synthetic cannabinoids in hair[J].J Forensic Med, 2021, 37(4):479
[9] MINAKATA K, YAMAGISHI I, NOZAWA H, et al. Sensitive identification and quantitation of parent forms of six synthetic cannabinoids in urine samples of human cavers by liquid chromatography-tandem mass spectrometry[J].Forensic Toxic, 2017, 35(2):275
[10] KANEKO S. Motor vehicle collisions caused by the‘super-strength'synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014[J].Forensic Toxic, 2017, 35(2):244
[11] LEONG HS, WATANABE S, KUZHIUMPARAMBIL U, et al. Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples[J].Forensic Toxic, 2021, 39(1):198
[12] FAN Y, ZONG X, LIU J, et al. Development of a fragmentation pattern of synthetic cannabinoids based on electrospray ionization mass spectrometry in positive ion mode to screen synthetic cannabinoids in illicit products[J].J Pharm Biomed Anal, 2020, 193: 113723
[13] 杨飞, 董露斌, 蔡嘉文. 电子烟油中新型合成大麻素检测分析[J].中国法医学杂志, 2021, 36(2):481
YANG F, DONG LB, CAI JW. Detection and analysis of new synthetic cannabinoids in electronic cigarette oil[J].Chin J Forensic Med, 2021, 36(5):481
[14] AKUTSU M, SUGIE K, SAITO K. Analysis of 62 synthetic cannabinoids by gaschromatography-mass spectrometry with photoionization[J].Froensic Toxic, 2017, 35(1):94
[15] MERCIECA G, ODOARDI S, MESTRIA S, et al. Application of ultrasound-assisted liquid-liquid microextraction coupled with gas chromatography and mass spectrometry for the rapid determination of synthetic cannabinoids and metabolites in biological samples[J].J Sep Sci, 43(14):2858
[16] LI H, QIAN ZH, ZHAO YB, et al. Study on the metabolic process of synthetic cannabinoids 4F-MDMB-BINACA and 4F-MDMB-BICA in human liver microsome and zebrafsh model via UHPLC-QE Orbitrap MS[J].Anal Bioanal Chem, 2022, 414(13):3905
[17] 梁冰清, 朱珺, 郑璐璐. 黄酮类化合物对托莫西汀体外代谢的影响[J].药物分析杂志, 2020, 40(7):1226
LIANG BQ, ZHU Z, ZHENG LL. Effect of flavonoids on the metabolism of atomoxetine in vitro[J].Chin J Pharm Anal, 2020, 40(7):1226
[18] 岳琳娜, 严慧, 向平, 等. 液相色谱-四极杆/静电场轨道阱高分辨质谱鉴定一种新精神活性物5F-MDMB-PICA在斑马鱼体内的代谢产物[J].分析测试学报, 2021, 40(5):690
YUE LN, YAN H, XIANG P, et al. Investigation on metabolites of 5F-MDMB-PICA in zebrafish by liquid chromatography-quadrupe/orbitrap mass spectrometry[J].J Instrum Anal, 2021, 40(5):690
