Phase I metabolism of the highly potent synthetic cannabinoid MDMB-CHMICA and detection in human urine samples
Phase I metabolism of the highly potent synthetic cannabinoid MDMB-CHMICA and detection in human urine samples
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DOI：
10.1002/dta.2049
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发表时间：
2017-05-01
影响因子：
2.9
通讯作者：
Auwaerter, Volker
中科院分区：
文献类型：
--
作者：
Franz, Florian;Angerer, Verena;Auwaerter, Volker
在最近出现的合成大麻素中，MDMB-CHMICA（N-{[1-(环己基甲基)-1H-吲哚-3-基]羰基}-3甲基缬氨酸甲酯）在中毒病例中的发病率非常高，因此需要能够检测药物摄取的分析方法。在本研究中，使用液相色谱-电喷雾电离-串联质谱（LC-ESI-MS/MS）和液相色谱-电喷雾电离-四极杆飞行时间质谱（LC-ESI-Q ToF-MS）技术研究了MDMB-CHMICA的体内I相代谢。主要代谢物是通过甲酯的水解和环己基甲基侧链的氧化形成的。建议一种单羟基化代谢物、酯水解产物和酯水解产物的另外两种羟基化代谢物作为尿液中选择性和灵敏检测的合适靶标。所有检测到的体内代谢物都可以使用人肝微粒体测定在体外进行验证。两种假定的主要代谢物已成功纳入合成大麻素代谢物的综合 LC-ESI-MS/MS 筛选方法中。对 5717 份真实尿样的筛查结果显示 818 例确诊使用 MDMB-CHMICA（14%）。由于最常见的给药途径是吸烟，因此对烟雾冷凝物进行了分析，以确定相关的热降解产物。甲酯和酰胺键的热解裂解导致降解产物，这些产物也是通过代谢形成的。这在头发分析中尤其重要，其中代谢物的检测通常被认为是消耗的证据。此外，通过 cAMP 积累测定测定了 MDMB-CHMICA 对 CB1 受体的内在活性，并表明该化合物是一种有效的完全激动剂。根据收集的数据，有助于对尿液和头发的分析结果进行增强解释。版权所有 (C) 2016 约翰·威利父子有限公司
Among the recently emerged synthetic cannabinoids, MDMB-CHMICA (methyl N-{[1-(cyclohexylmethyl)-1H-indol-3-yl] carbonyl}-3methylvalinate) shows an extraordinarily high prevalence in intoxication cases, necessitating analytical methods capable of detecting drug uptake. In this study, the in vivo phase I metabolism of MDMB-CHMICA was investigated using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry (LC-ESI-Q ToF-MS) techniques. The main metabolites are formed by hydrolysis of the methyl ester and oxidation of the cyclohexyl methyl side chain. One monohydroxylated metabolite, the ester hydrolysis product and two further hydroxylated metabolites of the ester hydrolysis product are suggested as suitable targets for a selective and sensitive detection in urine. All detected in vivo metabolites could be verified in vitro using a human liver microsome assay. Two of the postulatedmainmetabolites were successfully included in a comprehensive LC-ESI-MS/ MS screening method for synthetic cannabinoid metabolites. The screening of 5717 authentic urine samples resulted in 818 cases of confirmed MDMB-CHMICA consumption (14%). Since the most common route of administration is smoking, smoke condensates were analyzed to identify relevant thermal degradation products. Pyrolytic cleavage of the methyl ester and amide bond led to degradation productswhich were also formedmetabolically. This is particularly important in hair analysis, where detection ofmetabolites is commonly considered a proof of consumption. In addition, intrinsic activity of MDMB-CHMICA at the CB1 receptor was determined applying a cAMP accumulation assay and showed that the compound is a potent full agonist. Based on the collected data, an enhanced interpretation of analytical findings in urine and hair is facilitated. Copyright (C) 2016 John Wiley & Sons, Ltd.