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

被引:27
作者
Astrand, Anna [1 ]
Toreskog, Amanda [2 ]
Watanabe, Shimpei [2 ]
Kronstrand, Robert [1 ,2 ]
Green, Henrik [1 ,2 ]
Vikingsson, Svante [1 ,2 ]
机构
[1] Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden
[2] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden
关键词
Fentanyl analogs; Metabolism; Human hepatocytes; LC-QTOF-MS; MASS; IDENTIFICATION; ACRYLFENTANYL; FURANYLFENTANYL; ACETYLFENTANYL; GAS;
D O I
10.1007/s00204-018-2330-9
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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.
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收藏
页码:95 / 106
页数:12
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