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In Vitro and In Vivo Metabolite Identification Studies for the New Synthetic Opioids Acetylfentanyl, Acrylfentanyl, Furanylfentanyl, and 4-Fluoro-Isobutyrylfentanyl
UTS, Australia.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
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2017 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 19, no 4, 1102-1122 p.Article in journal (Refereed) Published
Abstract [en]

New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoro-isobutyrylfentanyl, and furanylfentanyl. All compounds were incubated at 10 mu M with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed. Data acquisition was performed in data-dependent acquisition mode during liquid chromatography high-resolution mass spectrometry analyses. Data was analyzed (1) manually based on predicted biotransformations and (2) with MetaSense software using data-driven search algorithms. Acetylfentanyl, acrylfentanyl, and 4-fluoro-isobutyrylfentanyl were predominantly metabolized by N-dealkylation, cleaving off the phenethyl moiety, monohydroxylation at the ethyl linker and piperidine ring, as well as hydroxylation/methoxylation at the phenyl ring. In contrast, furanylfentanyls major metabolites were generated by amide hydrolysis and dihydrodiol formation, while the nor-metabolite was minor or not detected in case samples at all. In general, in vitro results matched the in vivo findings well, showing identical biotransformations in each system. Phase II conjugation was observed, particularly for acetylfentanyl. Based on our results, we suggest the following specific and abundant metabolites as analytical targets in urine: a hydroxymethoxy and monohydroxylated metabolite for acetylfentanyl, a monohydroxy and dihydroxy metabolite for acrylfentanyl, two monohydroxy metabolites and a hydroxymethoxy metabolite for 4-fluoro-isobutyrylfentanyl, and a dihydrodiol metabolite and the amide hydrolysis metabolite for furanylfentanyl.

Place, publisher, year, edition, pages
SPRINGER , 2017. Vol. 19, no 4, 1102-1122 p.
Keyword [en]
authentic human urine samples; fentanyl analogs; human hepatocytes; LC-HRMS; metabolite identification
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-139392DOI: 10.1208/s12248-017-0070-zISI: 000404133800018PubMedID: 28382544OAI: oai:DiVA.org:liu-139392DiVA: diva2:1129880
Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2017-09-12

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The full text will be freely available from 2018-04-05 12:53
Available from 2018-04-05 12:53

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Vikingsson, SvanteGreen, HenrikKronstrand, RobertWohlfarth, Ariane
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