In vitro phase I metabolism of the synthetic cannabimimetic JWH-018
In vitro phase I metabolism of the synthetic cannabimimetic JWH-018
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DOI：
10.1007/s00216-010-4171-0
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发表时间：
2010-11-01
影响因子：
4.3
通讯作者：
Bender, Katja
中科院分区：
文献类型：
--
作者：
Wintermeyer, Annette;Moeller, Ines;Bender, Katja
一种有效的合成大麻素受体激动剂 JHW-018 最近被发现是滥用香料（如香料和其他草药混合物）中最重要的活性剂之一。 JWH-018 的高药理学和成瘾效力凸显了阐明 JWH-018 代谢的重要性，否则就不可能对其药代动力学和毒性进行有意义的了解。在本研究中，JWH-018与人肝微粒体体外孵育后，进行了细胞色素P450 I相代谢物的研究，随后进行了液相色谱-串联质谱分析。这揭示了萘环系统、吲哚部分和烷基侧链的单羟基化。另外，观察到萘环系和吲哚部分的二羟基化，或者作为萘环系和吲哚部分或烷基侧链的单羟基化的组合的结果，或者吲哚环系和烷基侧链的单羟基化的组合的结果。还有证据表明分子中羟基的不同位置存在三羟基化。此外，还发现烷基侧链的脱水与单羟基化和二羟基化相结合，以及萘环系统的芳烃氧化与不同氧化位点的单羟基化和二羟基化相结合。检测到N-脱烷基化还与N-脱烷基化代谢物的单羟基化和二氢二醇形成相结合。最后，发现代谢物在烷基侧链处羧化。
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.