Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

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• 作者：Ariane Wohlfarth ; Marisol S. Castaneto ; Mingshe Zhu ; Shaokun Pang…
• 关键词：5 ; fluoro ; AB ; PINACA ; AB ; PINACA ; in silico prediction ; metabolism ; synthetic cannabinoids
• 刊名：The AAPS Journal
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：17
• 期：3
• 页码：660-677
• 全文大小：1,053 KB
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• 作者单位：Ariane Wohlfarth (1)
  Marisol S. Castaneto (1)
  Mingshe Zhu (2)
  Shaokun Pang (3)
  Karl B. Scheidweiler (1)
  Robert Kronstrand (4) (5)
  Marilyn A. Huestis (1)
  
  1. Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland, 21224, USA
  2. Department of Biotransformation, Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, 08543, USA
  3. AB SCIEX, Redwood City, California, 94404, USA
  4. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, 58758, Link?ping, Sweden
  5. Division of Drug Research, Link?ping University, 58185, Link?ping, Sweden
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Biotechnology; Pharmacy;
• 出版者：Springer US
• ISSN：1550-7416

文摘

Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs-major metabolites?usually are 5-hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1?μmol/L of each compound was incubated with human liver microsomes for up to 1?h, and for metabolite profiling, 10?μmol/L was incubated with pooled human hepatocytes for up to 3?h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB-PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA.