利用人体肝细胞、肝微粒体和内部合成的参照物对 ADB-P-5Br-INACA 和 ADB-4en-P-5Br-INACA 进行体外代谢研究。

IF 2.6 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Drug Testing and Analysis Pub Date : 2024-07-23 DOI:10.1002/dta.3773
Tobias Rautio, Robin Obrist, Lucas Krebs, Therése Klingstedt, Johan Dahlén, Xiongyu Wu, Henrik Gréen
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引用次数: 0

摘要

合成大麻素(SC)仍然是一个重大的公共卫生问题,因为它们不断与世界各地的严重中毒和与毒品有关的死亡联系在一起。由于非法药物市场上不断出现新的合成大麻素,因此需要了解合成大麻素的代谢情况,以确定可作为法医毒理学筛选生物标志物的已形成代谢物,并了解药物的药代动力学。在这项工作中,研究了 ADB-4en-P-5Br-INACA 和 ADB-P-5Br-INACA ((S)-N-(1-氨基-3,3-二甲基-1-氧代丁-2-基)-5-溴-1-(戊-4-烯-1-基)-1H-吲唑-3-甲酰胺)的代谢、(S)-N-(1-氨基-3,3-二甲基-1-氧代丁-2-基)-5-溴-1-戊基-1H-吲唑-3-甲酰胺)进行了研究。这两种 SC 与汇集的人类肝细胞培养 3 小时,目的是使用液相色谱-四极杆飞行时间质谱法(LC-QTOF-MS)鉴定独特而丰富的代谢物。共鉴定出 ADB-4en-P-5Br-INACA 的 9 种代谢物和 ADB-P-5Br-INACA 的 10 种代谢物。观察到的生物转化包括二氢二醇形成、末端酰胺水解、羟基化、脱氢、羰基形成、葡萄糖醛酸化及其组合。主要代谢物已由内部合成的参考物证实。ADB-P-5Br-INACA 和 ADB-4en-P-5Br-INACA 的推荐生物标记物分别是末端羟基和二氢二醇代谢物。
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In vitro metabolism study of ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA using human hepatocytes, liver microsomes, and in-house synthesized references.

Synthetic cannabinoids (SCs) remain a major public health concern, as they continuously are linked to severe intoxications and drug-related deaths worldwide. As new SCs continue to emerge on the illicit drug market, an understanding of SC metabolism is needed to identify formed metabolites that may serve as biomarkers in forensic toxicology screening and for understanding the pharmacokinetics of the drugs. In this work, the metabolism of ADB-4en-P-5Br-INACA and ADB-P-5Br-INACA ((S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-5-bromo-1-pentyl-1H-indazole-3-carboxamide respectively) were investigated using human hepatocytes in vitro and in-house synthesized references. Both SCs were incubated with pooled human hepatocytes over 3 h, with the aim to identify unique and abundant metabolites using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In total nine metabolites were identified for ADB-4en-P-5Br-INACA and 10 metabolites for ADB-P-5Br-INACA. The observed biotransformations included dihydrodiol formation, terminal amide hydrolysis, hydroxylation, dehydrogenation, carbonyl formation, glucuronidation, and combinations thereof. The major metabolites were confirmed by in-house synthesized references. Recommended biomarkers for ADB-P-5Br-INACA and ADB-4en-P-5Br-INACA are the terminal hydroxy and dihydrodiol metabolite respectively.

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来源期刊
Drug Testing and Analysis
Drug Testing and Analysis BIOCHEMICAL RESEARCH METHODS-CHEMISTRY, ANALYTICAL
CiteScore
5.90
自引率
24.10%
发文量
191
审稿时长
2.3 months
期刊介绍: As the incidence of drugs escalates in 21st century living, their detection and analysis have become increasingly important. Sport, the workplace, crime investigation, homeland security, the pharmaceutical industry and the environment are just some of the high profile arenas in which analytical testing has provided an important investigative tool for uncovering the presence of extraneous substances. In addition to the usual publishing fare of primary research articles, case reports and letters, Drug Testing and Analysis offers a unique combination of; ‘How to’ material such as ‘Tutorials’ and ‘Reviews’, Speculative pieces (‘Commentaries’ and ‘Perspectives'', providing a broader scientific and social context to the aspects of analytical testing), ‘Annual banned substance reviews’ (delivering a critical evaluation of the methods used in the characterization of established and newly outlawed compounds). Rather than focus on the application of a single technique, Drug Testing and Analysis employs a unique multidisciplinary approach to the field of controversial compound determination. Papers discussing chromatography, mass spectrometry, immunological approaches, 1D/2D gel electrophoresis, to name just a few select methods, are welcomed where their application is related to any of the six key topics listed below.
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