title: Metabolite profiling of RCS-4, a novel synthetic cannabinoid designer drug, using human hepatocyte metabolism and TOF-MS.
abstract: BACKGROUND
  Since 2009, scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) is a potent cannabinoid receptor agonist sold in herbal smoking blends. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations. Materials & methods & Results: With 1 h human hepatocyte incubation and TOF high-resolution MS, we identified 18 RCS-4 metabolites, many not yet reported. Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite.
  
  
  CONCLUSIONS
  For the first time, we present a metabolic scheme of RCS-4 obtained from human hepatocytes, including Phase I and II metabolites. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods.
authors.affiliation: Chemistry & Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Adarsh S
authors.initials: AS
authors.lastname: Gandhi
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.forename: Shaokun
authors.initials: S
authors.lastname: Pang
authors.forename: Ariane
authors.initials: A
authors.lastname: Wohlfarth
authors.forename: Karl B
authors.initials: KB
authors.lastname: Scheidweiler
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; D013058:Mass Spectrometry / Q000379:methods*
chemical_list: D002186:Cannabinoids; D015198:Designer Drugs