Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry

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• 作者：Marisol S. Castaneto ; Ariane Wohlfarth ; Shaokun Pang ; Mingshe Zhu…
• 关键词：AB ; FUBINACA ; Metabolite profiling ; HRMS ; Hepatocytes ; In silico
• 刊名：Forensic Toxicology
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：33
• 期：2
• 页码：295-310
• 全文大小：1,122 KB
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• 作者单位：Marisol S. Castaneto (1) (2)
  Ariane Wohlfarth (1)
  Shaokun Pang (3)
  Mingshe Zhu (4)
  Karl B. Scheidweiler (1)
  Robert Kronstrand (5) (6)
  Marilyn A. Huestis (1)
  
  1. Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Suite 200 Room 05A-721, Baltimore, MD, 21224, USA
  2. Program in Toxicology, University of Maryland, School of Medicine, Baltimore, MD, USA
  3. SCIEX, Redwood City, CA, USA
  4. Department of Biotransformation, Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA
  5. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Link?ping University, Link?ping, Sweden
  6. Division of Drug Research, Department of Medical and Health Sciences, Link?ping University, Link?ping, Sweden
  
• 刊物主题：Forensic Medicine; Pharmacology/Toxicology; Medicinal Chemistry; Medicine/Public Health, general; Medical Law;
• 出版者：Springer Japan
• ISSN：1860-8973

文摘

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-FUBINACA’s 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?μmol/l, up to 1?h). The metabolite profile of human hepatocytes (10?μmol/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?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?software. AB-FUBINACA’s half-life in HLMs was 62.6?±?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.