Systematic In Vitro Metabolic Profiling of the OXIZID Synthetic Cannabinoids BZO-4en-POXIZID, BZO-POXIZID, 5F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID
Systematic In Vitro Metabolic Profiling of the OXIZID Synthetic Cannabinoids BZO-4en-POXIZID, BZO-POXIZID, 5F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID
复制标题
OXIZID 合成大麻素 BZO-4en-POXIZID、BZO-POXIZID、5F-BZO-POXIZID、BZO-HEXOXIZID 和 BZO-CHMOXIZID 的系统体外代谢分析
DOI：
10.1093/jat/bkad016
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发表时间：
2023
影响因子：
2.5
通讯作者：
Seto Yasuo
中科院分区：
文献类型：
--
作者：
Watanabe Shimpei;Baginski Steven;Iwai Takahiro;Matsushita Ritsuko;Takatsu Masahisa;Nakanishi Toshio;Lindbom Karin;Mckenzie Craig;Vikingsson Svante;Kronstrand Robert;Green Henrik;Seto Yasuo
一种名为OXIZID的新型合成大麻类药物最近出现在娱乐毒品市场上。为了继续在生物标本中检测新药物，代谢物的鉴定是必不可少的。本研究的目的是阐明BZO-4EN-POXIZID在人肝微粒体(HLMS)和人肝细胞孵育中产生的代谢产物，并在相同的实验装置下与密切相关的类似物进行比较。每种药物在HLM中孵育1 h，BZO-4EN-POXIZID在人肝细胞中孵育3 h，然后用高效液相色谱-高分辨质谱仪分析孵育产物。BZO-4EN-POXIZID代谢产物通过二氢二醇生成、羟化、烯键还原和葡萄糖醛酸化等代谢途径与HLMS和人肝细胞孵育得到。主要代谢途径是在戊烯基尾部形成二氢二醇。BZO-POXIZID、5- F-BZO-POXIZID、BZO-HEXOXIZID和BZO-CHMOXIZID的代谢途径与文献报道的相似，代谢途径为n-脱烷基、羟基化、成酮和氧化脱氟(为醇或羧酸)。结果表明，OXIZIDs主要在当时的烷基部分代谢，当当时的烷基部分是单烃时，主要的代谢途径是羟化，而当当时的烷基部分含有特定的官能团(烯烃或氟)时，优先选择官能团特定的途径(二氢二醇形成和氧化脱氟)，就像其他合成大麻素类一样。通过这些主要代谢途径产生的主要代谢物应作为尿液分析的有用分析目标。此外，葡萄糖醛酸化代谢物的较高丰度表明，尿液分析可能需要酶解葡萄糖醛酸苷以增加I相代谢物浓度并改进检测。
A new class of synthetic cannabinoids termed OXIZIDs has recently emerged on the recreational drug market. In order to continue the detection of new drugs in biological specimens, the identification of metabolites is essential. The aim of this study was to elucidate the metabolites of BZO-4en-POXIZID produced in human liver microsomes (HLMs) and human hepatocyte incubations and to compare the results with closely related analogs using the same experimental setup. Each drug was incubated for 1 h in HLM and BZO-4en-POXIZID was also incubated in human hepatocytes for up to 3 h. Subsequently, the incubates were analyzed by liquid chromatography–high-resolution mass spectrometry. BZO-4en-POXIZID metabolites were obtained in the incubation with HLMs and human hepatocytes, via the metabolic pathways of dihydrodiol formation, hydroxylation, reduction of the alkene bond and glucuronidation. The major metabolic pathway was found to be dihydrodiol formation at the pentenyl tail moiety. BZO-POXIZID, 5 F-BZO-POXIZID, BZO-HEXOXIZID and BZO-CHMOXIZID underwent similar metabolism to those reported in the literature, via the metabolic pathways ofN-dealkylation, hydroxylation, ketone formation and oxidative defluorination (to alcohol or carboxylic acid). The results suggest that OXIZIDs are mainly metabolized at theN-alkyl moiety and the major metabolic pathways are hydroxylation when theN-alkyl moiety is a simple hydrocarbon, whereas functional-group-specific pathways (dihydrodiol formation and oxidative defluorination) are preferred when the moiety contains specific functional groups (alkene or fluoro), as has been observed for other synthetic cannabinoids. The major metabolites generated via these major metabolic pathways should serve as useful analytical targets for urine analysis. Furthermore, the higher abundance of glucuronidated metabolite suggests that enzymatic hydrolysis of glucuronides may be necessary for urine analysis to increase phase I metabolite concentration and improve detection.