title: First metabolic profile of XLR-11, a novel synthetic cannabinoid, obtained by using human hepatocytes and high-resolution mass spectrometry.
abstract: BACKGROUND
  Since the mid-2000s synthetic cannabinoids have been abused as recreational drugs, prompting scheduling of these substances in many countries. To circumvent legislation, manufacturers constantly market new compounds; [1-(5-fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11), the fluorinated UR-144 analog, is one of the most recent and widely abused drugs, and its use is now linked with acute kidney injury. Our goal was to investigate XLR-11 metabolism for identification of major urinary targets in analytical methods and to clarify the origin of metabolites when one or more parent synthetic cannabinoids can be the source.
  
  
  METHODS
  We incubated 10 μmol/L XLR-11 with pooled human hepatocytes and sampled after 1 and 3 h. Samples were analyzed by high-resolution mass spectrometry with a TOF scan followed by information-dependent acquisition triggered product ion scans with dynamic background subtraction and mass defect filters. Scans were thoroughly data mined with different data processing algorithms (Metabolite Pilot 1.5).
  
  
  RESULTS
  XLR-11 underwent phase I and II metabolism, producing more than 25 metabolites resulting from hydroxylation, carboxylation, hemiketal and hemiacetal formation, internal dehydration, and further glucuronidation of some oxidative metabolites. No sulfate or glutathione conjugation was observed. XLR-11 also was defluorinated, forming UR-144 metabolites. On the basis of mass spectrometry peak areas, we determined that the major metabolites were 2'-carboxy-XLR-11, UR-144 pentanoic acid, 5-hydroxy-UR-144, hydroxy-XLR-11 glucuronides, and 2'-carboxy-UR-144 pentanoic acid. Minor metabolites were combinations of the biotransformations mentioned above, often glucuronidated.
  
  
  CONCLUSIONS
  These are the first data defining major urinary targets of XLR-11 metabolism that could document XLR-11 intake in forensic and clinical investigations.
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD;
authors.forename: Ariane
authors.initials: A
authors.lastname: Wohlfarth
authors.forename: Shaokun
authors.initials: S
authors.lastname: Pang
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.forename: Adarsh S
authors.initials: AS
authors.lastname: Gandhi
authors.forename: Karl B
authors.initials: KB
authors.lastname: Scheidweiler
authors.forename: Hua-fen
authors.initials: HF
authors.lastname: Liu
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D002186:Cannabinoids / Q000378:metabolism*; D015198:Designer Drugs / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry / Q000379:methods
chemical_list: D002186:Cannabinoids; D015198:Designer Drugs; C585106:XLR-11