Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Suite 200, Room 05A-721, Baltimore, Maryland, 21224, USA.
AAPS J. 2013 Oct;15(4):1091-8. doi: 10.1208/s12248-013-9516-0. Epub 2013 Aug 3.
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.
自联邦当局将第一批合成大麻素 JWH-018 和 JWH-073 列入管制后，新的合成大麻素便迅速面世。N-(1-金刚烷基)-1-戊基-1H-吲唑-3-甲酰胺（AKB-48），也被称为 APINACA，最近在日本草药吸食混合物中被发现。从 2010 年 3 月到 2013 年 1 月，美国国家法医实验室信息系统共登记了 443 例 AKB-48 案件报告。2013 年 5 月，美国缉毒署将 AKB-48 列为附表 I 管制药物。最近的研究表明，AKB-48 与 CB1 受体的结合亲和力是 CB2 的两倍。这些药理作用以及在尿液中难以检测到母体化合物，突出了鉴定代谢物对于开发用于临床和法医调查的分析方法的重要性。本研究利用人源肝细胞和三重四极杆飞行时间质谱，鉴定了 17 种新型 AKB-48 的 I 相和 II 相代谢物，它们是在脂肪族金刚烷环或 N-戊基侧链上发生单羟基化、二羟基化或三羟基化的产物。一些单羟基化和二羟基化代谢物还发生了葡萄糖醛酸化缀合。金刚烷环和 N-戊基侧链上的氧化和二羟基化形成了酮。孵育 3 小时后鉴定出的代谢物多于孵育 1 小时。这是首次从人源肝细胞和高分辨率质谱获得 AKB-48 的代谢途径。这些数据对于开发用于在临床和法医检测中鉴定 AKB-48 消耗的分析方法是必要的。
