Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18.
Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18.
复制标题
合成大麻素 NNEI 和 MN-18 的动力学和代谢特征。
DOI：
10.1002/dta.2262
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发表时间：
2018
影响因子：
2.9
通讯作者：
Thomas,BrianF
中科院分区：
文献类型：
--
作者：
Kevin,RichardC;Lefever,TimothyW;Snyder,RodneyW;Patel,PurviR;Gamage,ThomasF;Fennell,TimothyR;Wiley,JennyL;McGregor,IainS;Thomas,BrianF
2014年和2015年，在多个国家的再利用和滥用产品中检测到合成大麻受体激动剂Nnei(N‐1‐naphthalenyl‐1‐pentyl‐1H‐indole‐3‐carboxamide)和MN-18(N‐1‐naphthalenyl‐1‐pentyl‐1H‐indazole‐3‐carboxamide)，并与中毒和中毒事件有关。尽管如此，NNEI和MN-18的药代动力学特征尚未确定。在本研究中，NNEI和MN-18分别在大鼠和人肝微粒体和肝细胞中孵育，以估计动力学参数和确定潜在的代谢途径。NNEI和MN-18可被大鼠和人肝微粒体迅速清除，并在与大鼠和人肝细胞孵育过程中发生一系列的氧化转化。几种独特的代谢物被鉴定用于NNEI和MN-18摄入量的法医鉴定。有趣的是，NNEI经历了更多的生物转化(20种NNEI代谢物比10种MN-18代谢物)，但母体MN-18在体内的消除速度比NNEI快。此外，在体内的消除比体外估计的更快。这些数据突出表明，即使是密切相关的合成大麻素也可以具有明显不同的药代动力学特征，在体外和活体模型之间可以有很大的不同。
In 2014 and 2015, synthetic cannabinoid receptor agonists NNEI (N‐1‐naphthalenyl‐1‐pentyl‐1H‐indole‐3‐carboxamide) and MN‐18 (N‐1‐naphthalenyl‐1‐pentyl‐1H‐indazole‐3‐carboxamide) were detected in recreationally used and abused products in multiple countries, and were implicated in episodes of poisoning and toxicity. Despite this, the pharmacokinetic profiles of NNEI and MN‐18 have not been characterized. In the present study NNEI and MN‐18 were incubated in rat and human liver microsomes and hepatocytes, to estimate kinetic parameters and to identify potential metabolic pathways, respectively. These parameters and pathways were then examinedin vivo, via analysis of blood and urine samples from catheterized male rats following intraperitoneal (3 mg/kg) administration of NNEI and MN‐18. Both NNEI and MN‐18 were rapidly cleared by rat and human liver microsomes, and underwent a range of oxidative transformations during incubation with rat and human hepatocytes. Several unique metabolites were identified for the forensic identification of NNEI and MN‐18 intake. Interestingly, NNEI underwent a greater number of biotransformations (20 NNEI metabolitesversus10 MN‐18 metabolites), yet parent MN‐18 was eliminated at a faster rate than NNEIin vivo. Additionally,in vivoelimination was more rapid thanin vitroestimates. These data highlight that even closely related synthetic cannabinoids can possess markedly distinct pharmacokinetic profiles, which can vary substantially betweenin vitroandin vivomodels.