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Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry
NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
NIDA, MD 21224 USA.
Bristol Myers Squibb Co, NJ USA.
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2015 (English)In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 33, no 2, 295-310 p.Article in journal (Refereed) Published
Abstract [en]

AB-FUBINACA, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide, is an indazole synthetic cannabinoid identified in drug seizures around the world. Few metabolism data are available, despite the need for human urinary markers to detect AB-FUBINACA intake. Our main objective was to identify suitable analytical targets by analyzing human hepatocyte incubation samples with high-resolution mass spectrometry (HRMS) and to confirm the results in authentic urine specimens. We also determined AB-FUBINACAs metabolic stability in human liver microsomes (HLMs) and compared hepatocyte and urine results with in silico predictions. The metabolic stability of AB-FUBINACA was determined in pooled HLMs (1 A mu mol/l, up to 1 h). The metabolite profile of human hepatocytes (10 A mu mol/l, 1 and 3 h) and urine samples from two subjects were determined by HRMS using information-dependent tandem-mass spectrometry (MS-MS) acquisition. Data were analyzed with MetabolitePilot (TM) software utilizing different processing algorithms, including generic peak finding, mass defect filtering, neutral loss, and product ion filtering. In silico metabolite prediction was performed with MetaSite (TM) software. AB-FUBINACAs half-life in HLMs was 62.6 +/- A 4.0 min. AB-FUBINACA produced 11 metabolites (2 glucuronides) in human hepatocytes and 10 were identified in authentic human urine. Major metabolic pathways were terminal amide hydrolysis, acyl glucuronidation and hydroxylation at the aminooxobutane moiety. Epoxidation followed by hydrolysis, hydroxylation at the indazole moiety and dehydrogenation were minor pathways. Defluorination did not occur. Seventeen first-generation metabolites were predicted in silico, of which seven were observed in vitro and eight in vivo. We recommend AB-FUBINACA carboxylic acid, hydroxy AB-FUBINACA carboxylic acid, dihydrodiol AB-FUBINACA and dihydrodiol AB-FUBINACA carboxylic acid as suitable urinary markers.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2015. Vol. 33, no 2, 295-310 p.
Keyword [en]
AB-FUBINACA; Metabolite profiling; HRMS; Hepatocytes; In silico
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-120458DOI: 10.1007/s11419-015-0275-8ISI: 000358055400010OAI: diva2:845569

Funding Agencies|National Institute on Drug Abuse, National Institutes of Health

Available from: 2015-08-12 Created: 2015-08-11 Last updated: 2016-04-24

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Kronstrand, Robert
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Faculty of Medicine and Health SciencesDivision of Drug Research
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