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

• Published in: Archives of toxicology 2019-01, Vol.93 (1), p.95-106
• Main Authors: Åstrand, Anna, Töreskog, Amanda, Watanabe, Shimpei, Kronstrand, Robert, Gréen, Henrik, Vikingsson, Svante
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - metabolism; Analogs; Biomedical and Life Sciences; Biomedicine; Biotransformation; Carbon; Cells, Cultured; Chromatography, High Pressure Liquid; Cryopreservation; Dealkylation; Environmental Health; Fentanyl; Fentanyl - analogs & derivatives; Fentanyl - metabolism; Hepatocytes; Hepatocytes - metabolism; Humans; Liquid chromatography; Mass Spectrometry; Mass spectroscopy; Metabolism; Metabolites; Molecular Structure; Occupational Medicine/Industrial Medicine; Organic compounds; Overdose; Oxidation; Pharmacology/Toxicology; Piperidine; Quadrupoles; Ring structures; Structural members; Subgroups; Substructures; Toxicokinetics and Metabolism
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-018-2330-9

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 µM were incubated with cryopreserved human hepatocytes (1 × 10 6 cells/mL) for 0, 1, 3 and 5 h. 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.