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Looking at flubromazolam metabolism from four different angles: Metabolite profiling in human liver microsomes, human hepatocytes, mice and authentic human urine samples with liquid chromatography high-resolution mass spectrometry.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758 Linköping, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758 Linköping, Sweden.
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758 Linköping, Sweden.
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2017 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 274, 55-63 p.Article in journal (Refereed) Published
Abstract [en]

Flubromazolam is a triazolam benzodiazepine that recently emerged as a new psychoactive substance. Since metabolism data are scarce and good analytical targets besides the parent are unknown, we investigated flubromazolam metabolism in vitro and in vivo. 10μmol/L flubromazolam was incubated with human liver microsomes for 1h and with cryopreserved human hepatocytes for 5h. Mice were administered 0.5 or 1.0mg flubromazolam/kg body weight intraperitoneally, urine was collected for 24h. All samples, together with six authentic forensic human case specimens, were analyzed (with or without hydrolysis, in case it was urine) by UHPLC-HRMS on an Acquity HSS T3 column with an Agilent 6550 QTOF. Data mining was performed manually and with MassMetasite software (Molecular Discovery). A total of nine metabolites were found, all generated by hydroxylation and/or glucuronidation. Besides O-glucuronidation, flubromazolam formed an N(+)-glucuronide. Flubromazolam was not metabolized extensively in vitro, as only two monohydroxy metabolites were detected in low intensity in hepatocytes. In the mice samples, seven metabolites were identified, which mostly matched the metabolites in the human samples. However, less flubromazolam N(+)-glucuronide and an additional hydroxy metabolite were observed. The six human urine specimens showed different extent of metabolism: some samples had an intense flubromazolam peak next to a minute signal for a monohydroxy metabolite, others showed the whole variety of hydroxylated and glucuronidated metabolites. Overall, the most abundant metabolite was a monohydroxy metabolite, which we propose as α-hydroxyflubromazolam based on MSMS fragmentation. These metabolism data will assist in interpretation and analytical method development.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 274, 55-63 p.
Keyword [en]
Designer benzodiazepine, Flubromazolam, High resolution mass spectrometry, Metabolism
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-136123DOI: 10.1016/j.forsciint.2016.10.021ISI: 000401098800010PubMedID: 27863836OAI: oai:DiVA.org:liu-136123DiVA: diva2:1085195
Note

Funding agencies: Linkoping Center of Forensic Science [2-2014]; Strategic Research Area Forensic Sciences (Strategiomradet Forensiska Vetenskaper) at Linkoping University

Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2017-06-13Bibliographically approved

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Wohlfarth, ArianeVikingsson, SvanteKugelberg, Fredrik CGreen, HenrikKronstrand, Robert
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CiteExportLink to record
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