First Characterization of AKB-48 Metabolism, a Novel Synthetic Cannabinoid, Using Human Hepatocytes and High-Resolution Mass Spectrometry
First Characterization of AKB-48 Metabolism, a Novel Synthetic Cannabinoid, Using Human Hepatocytes and High-Resolution Mass Spectrometry
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DOI：
10.1208/s12248-013-9516-0
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发表时间：
2013-10-01
期刊：
影响因子：
4.5
通讯作者：
Huestis, Marilyn A.
中科院分区：
文献类型：
--
作者：
Gandhi, Adarsh S.;Zhu, Mingshe;Huestis, Marilyn A.
自从联邦当局安排了第一批合成大麻素JWH-018和JWH-073的上市以来，新的合成大麻素被大量投放市场。N-(1-Adamantyl)-1-pentylindazole-3-carboxamide(AKB-48)，也被称为APINACA，最近在日本草药吸烟混合物中被发现。从2010年3月到2013年1月，国家法医实验室信息系统在美国登记了443起AKB-48病例报告。2013年5月，美国药品监督管理局将AKB-48列为I类药物。最近发现，AKB-48与CB1受体的结合亲和力是CB2的两倍。这些药理作用和在尿液中检测母体化合物的困难突出了代谢物鉴定对于开发临床和法医调查的分析方法的重要性。利用人肝细胞和TripleTOF质谱仪，我们鉴定了17种新的I相和II相AKB-48代谢物，它们是脂肪族金刚烷环或N-戊基侧链上单羟化、双羟化或三羟基化的产物。一些单羟基代谢物和二羟基代谢物的葡萄糖醛酸化物结合也发生了。金刚烷环和N-戊基侧链上的氧化和二羟基化形成酮。孵育3h的代谢产物多于孵育1h的代谢产物。我们首次提出了从人肝细胞和高分辨质谱仪获得的AKB-48代谢方案。需要这些数据来开发分析方法，以在临床和法医测试中确定AKB-48的消费量。
Since the federal authorities scheduled the first synthetic cannabinoids, JWH-018 and JWH-073, new synthetic cannabinoids were robustly marketed. N-(1-Adamantyl)-1-pentylindazole-3-carboxamide (AKB-48), also known as APINACA, was recently observed in Japanese herbal smoking blends. The National Forensic Laboratory Information System registered 443 reports of AKB-48 cases in the USA from March 2010 to January 2013. In May 2013, the Drug Enforcement Administration listed AKB-48 as a Schedule I drug. Recently, AKB-48 was shown to have twice the CB1 receptor binding affinity than CB2. These pharmacological effects and the difficulty in detecting the parent compound in urine highlight the importance of metabolite identification for developing analytical methods for clinical and forensic investigations. Using human hepatocytes and TripleTOF mass spectrometry, we identified 17 novel phase I and II AKB-48 metabolites, products of monohydroxylation, dihydroxylation, or trihydroxylation on the aliphatic adamantane ring or N-pentyl side chain. Glucuronide conjugation of some mono- and dihydroxylated metabolites also occurred. Oxidation and dihydroxylation on the adamantane ring and N-pentyl side chain formed a ketone. More metabolites were identified after 3 h of incubation than at 1 h. For the first time, we present a AKB-48 metabolic scheme obtained from human hepatocytes and high-resolution mass spectrometry. These data are needed to develop analytical methods to identify AKB-48 consumption in clinical and forensic testing.