Institute of Legal Medicine, Medical Faculty, University of Cologne, Melatengürtel 60-62, 50823 Cologne, Germany.
Anal Bioanal Chem. 2010 Nov;398(5):2141-53. doi: 10.1007/s00216-010-4171-0. Epub 2010 Sep 14.
A potent synthetic cannabinoid receptor agonist, JHW-018, was recently detected as one of the most prominent active agents in abusively used incenses such as Spice and other herbal blends. The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography-tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain.
一种强效合成大麻素受体激动剂 JHW-018，最近被检测为在滥用香薰如 Spice 及其他草药混合物中最主要的活性成分之一。JWH-018 的高药理学和成瘾潜力凸显了阐明其代谢途径的重要性，如果不进行这方面的研究，就不可能对其药代动力学和毒性有更深入的了解。在本研究中，在体外用人肝微粒体孵育 JWH-018 后，通过液相色谱-串联质谱分析，研究了 JWH-018 的细胞色素 P450 相 I 代谢物。结果显示萘环系统、吲哚部分和烷基侧链发生了单羟基化。此外，还观察到萘环系统和吲哚部分的二羟基化，或者是萘环系统和吲哚部分或烷基侧链的单羟基化的组合，或者是吲哚环系统和烷基侧链的单羟基化的组合。该分子中羟基的不同位置也有发生三羟基化的迹象。此外，还发现了烷基侧链的脱水反应，以及与单羟基化和二羟基化以及萘环系统的芳烃氧化的结合，与不同氧化部位的单羟基化和二羟基化的结合。还检测到 N-去烷基化与 N-去烷基代谢物的单羟基化和二羟化形成的结合。最后，发现一种在烷基侧链上发生羧化的代谢物。
