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在大鼠体内结构相关的合成大麻素 AMB-FUBINACA 和 AMB-CHMICA 的代谢和药代动力学行为的深入比较。

In-depth comparison of the metabolic and pharmacokinetic behaviour of the structurally related synthetic cannabinoids AMB-FUBINACA and AMB-CHMICA in rats.

机构信息

Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), University Jaume I, Avda. Sos Baynat s/n, 12071, Castellón, Spain.

Predepartmental Unit of Medicine, Unitat Mixta de Neuroanatomia Funcional NeuroFun-UVEG-UJI, University Jaume I, Castellón, Spain.

出版信息

Commun Biol. 2022 Feb 24;5(1):161. doi: 10.1038/s42003-022-03113-5.

DOI:10.1038/s42003-022-03113-5
PMID:35210552
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8873228/
Abstract

Synthetic cannabinoids receptor agonists (SCRAs) are often almost completely metabolised, and hence their pharmacokinetics should be carefully evaluated for determining the most adequate biomarker in toxicological analysis. Two structurally related SCRAs, AMB-FUBINACA and AMB-CHMICA, were selected to evaluate their in vivo metabolism and pharmacokinetics using male Sprague-Dawley rats. Brain, liver, kidney, blood (serum) and urine samples were collected at different times to assess the differences in metabolism, metabolic reactions, tissue distribution and excretion. Both compounds experimented O-demethyl reaction, which occurred more rapidly for AMB-FUBINACA. The parent compounds and O-demethyl metabolites were highly bioaccumulated in liver, and were still detected in this tissue 48 h after injection. The different indazole/indole N-functionalisation produced diverse metabolic reactions in this moiety and thus, different urinary metabolites were formed. Out of the two compounds, AMB-FUBINACA seemed to easily cross the blood-brain barrier, presenting higher brain/serum concentrations ratio than AMB-CHMICA.

摘要

合成大麻素受体激动剂（SCRAs）通常几乎完全被代谢，因此应仔细评估其药代动力学，以确定毒理学分析中最合适的生物标志物。选择两种结构相关的 SCRAs，AMB-FUBINACA 和 AMB-CHMICA，使用雄性 Sprague-Dawley 大鼠来评估它们的体内代谢和药代动力学。在不同时间采集脑、肝、肾、血液（血清）和尿液样本，以评估代谢、代谢反应、组织分布和排泄的差异。这两种化合物都经历了 O-去甲基反应，AMB-FUBINACA 发生的速度更快。母体化合物和 O-去甲基代谢物在肝脏中高度生物蓄积，并且在注射后 48 小时仍在该组织中检测到。不同的吲唑/吲哚 N-官能化在该部分产生不同的代谢反应，因此形成了不同的尿代谢物。在这两种化合物中，AMB-FUBINACA 似乎更容易穿过血脑屏障，其脑/血清浓度比 AMB-CHMICA 更高。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/1974bcf8df9f/42003_2022_3113_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/a91fad245d90/42003_2022_3113_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/c2372699586f/42003_2022_3113_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/b66782b1df6a/42003_2022_3113_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/dd9739477d71/42003_2022_3113_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/1974bcf8df9f/42003_2022_3113_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/a91fad245d90/42003_2022_3113_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/c2372699586f/42003_2022_3113_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/b66782b1df6a/42003_2022_3113_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/dd9739477d71/42003_2022_3113_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3020/8873228/1974bcf8df9f/42003_2022_3113_Fig5_HTML.jpg

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