In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA
In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA
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DOI：
10.1002/dta.1796
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发表时间：
2015-10-01
影响因子：
2.9
通讯作者：
van Nuijs, Alexander L. N.
中科院分区：
文献类型：
--
作者：
Erratico, Claudio;Negreira, Noelia;van Nuijs, Alexander L. N.
N-[（1 S）-1-（氨基羰基）-2-甲基丙基]-1-（环己基甲基）-1H-吲唑-3-甲酰胺（AB-CHMINACA）是最近引入的合成大麻素。目前，没有关于AB-CHMINACA在体外或体内人体代谢的信息。因此，筛选AB-CHMINACA消耗的生物监测研究缺乏关于靶向的潜在生物标志物（例如代谢物）的任何信息。为了弥补这一差距，我们研究了体外代谢的AB-CHMINACA使用人肝微粒体（HLM）。AB-CHMINACA代谢物的形成使用液相色谱法结合飞行时间质谱法监测。检测到AB-CHMINACA的26种代谢产物，包括7种单羟基化和6种二羟基化代谢产物以及由AB-CHMINACA的N-脱烷基化产生的代谢产物，所有代谢产物均由细胞色素P450（CYP）酶产生。还形成了两种羧化代谢产物（可能由酰胺酶产生）和五种葡萄糖醛酸化代谢产物。五种单羟基化和一种羧基化代谢物可能是检测到的主要代谢物。使用一组7种人重组CYP（rCYP）检测单个CYP参与AB-CHMINACA代谢物形成的情况。HLM产生的所有羟基化AB-CHMINACA代谢产物也由检测的rCYP产生，其中rCYP 3A 4是活性最高的酶。AB-CHMINACA的大多数体外代谢物也存在于从AB-CHMINACA使用者获得的尿液中，因此显示了使用体外代谢实验获得的结果的可靠性，所述体外代谢实验用于预测AB-CHMINACA的体内代谢。AB-CHMINACA代谢物在使用尿液样本的生物监测研究中的目标现在被可靠地识别，并可用于常规分析。版权所有（c）2015约翰威利父子有限公司
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (AB-CHMINACA) is a recently introduced synthetic cannabinoid. At present, no information is available about in vitro or in vivo human metabolism of AB-CHMINACA. Therefore, biomonitoring studies to screen AB-CHMINACA consumption lack any information about the potential biomarkers (e.g.metabolites) to target. To bridge this gap, we investigated the in vitro metabolism of AB-CHMINACA using human liver microsomes (HLMs). Formation of AB-CHMINACA metabolites was monitored using liquid chromatography coupled to time-of-flight mass spectrometry. Twenty-six metabolites of AB-CHMINACA were detected including seven mono-hydroxylated and six di-hydroxylated metabolites and a metabolite resulting from N-dealkylation of AB-CHMINACA, all produced by cytochrome P450 (CYP) enzymes. Two carboxylated metabolites, likely produced by amidase enzymes, and five glucuronidated metabolites were also formed. Five mono-hydroxylated and one carboxylated metabolite were likely the major metabolites detected. The involvement of individual CYPs in the formation of AB-CHMINACA metabolites was tested using a panel of seven human recombinant CYPs (rCYPs). All the hydroxylated AB-CHMINACA metabolites produced by HLMs were also produced by the rCYPs tested, among which rCYP3A4 was the most active enzyme. Most of the in vitro metabolites of AB-CHMINACA were also present in urine obtained from an AB-CHMINACA user, therefore showing the reliability of the results obtained using the in vitro metabolism experiments conducted to predict AB-CHMINACA in vivo metabolism. The AB-CHMINACA metabolites to target in biomonitoring studies using urine samples are now reliably identified and can be used for routine analysis. Copyright (c) 2015 John Wiley & Sons, Ltd.