Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS
Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS
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DOI：
10.1007/s00204-018-2330-9
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发表时间：
2019-01-01
影响因子：
6.1
通讯作者：
Vikingsson, Svante
中科院分区：
文献类型：
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作者：
Astrand, Anna;Toreskog, Amanda;Vikingsson, Svante
最近，在欧洲和美国，许多芬太尼类似物与服药过量死亡有关。到目前为止，人们对结构相关亚组的分子行为知之甚少。脂环族芬太尼。本研究将终浓度为 5 μM 的环丙基、环丁基、环戊基、环己基和 2,2,3,3-四甲基环丙基芬太尼 (TMCPF) 参考标准品与冷冻保存的人肝细胞 (1x10(6) 个细胞/mL) 孵育 0、1、3 和 5 小时。通过液相色谱-四极杆飞行时间质谱分析鉴定形成的代谢物。发现的最丰富的生物转化是 N-脱烷基化（正常代谢物的形成）和脂环族环的氧化。随着环尺寸的增加，N-脱烷基化的重要性降低，有利于脂环氧化。例如环丙基芬太尼，具有三碳环，其正常代谢物覆盖了总代谢峰面积的82%，并且没有观察到脂环族环的氧化。相比之下，TMCPF具有七碳环结构，其脂环上多达85%的代谢物被氧化。发现的其他生物转化包括哌啶乙基部分和/或苯乙基子结构的氧化、葡萄糖醛酸化以及酰胺水解以形成与去丙酰芬太尼相同的代谢物。总而言之，这项研究为了解摄入后形成的许多结构相关的芬太尼类似物的代谢提供了基础。
Recently, a number of fentanyl analogs have been implicated in overdose deaths in Europe and in the US. So far, little is known of the molecular behavior of the structurally related subgroup; the alicyclic fentanyls. In this study, reference standards of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2,2,3,3-tetramethylcyclopropyl fentanyl (TMCPF) at a final concentration of 5 mu M were incubated with cryopreserved human hepatocytes (1x10(6) cells/mL) for 0, 1, 3 and 5h. The metabolites formed were identified by liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The most abundant biotransformation found was N-dealkylation (formation of normetabolites) and oxidation of the alicyclic rings. As ring size increased, the significance of N-dealkylation decreased in favor of alicyclic ring oxidation. An example of this was cyclopropyl fentanyl, with a three-carbon ring, whose normetabolite covered 82% of the total metabolic peak area and no oxidation of the alicyclic ring was observed. In contrast, TMCPF, with a seven-carbon ring structure, rendered as much as 85% of its metabolites oxidized on the alicyclic ring. Other biotransformations found included oxidation of the piperidine ethyl moiety and/or the phenethyl substructure, glucuronidation as well as amide hydrolysis to form metabolites identical to despropionyl fentanyl. Taken together, this study provides a base for understanding the metabolism of a number of structurally related fentanyl analogs formed upon intake.