title: Phase I metabolism of the highly potent synthetic cannabinoid MDMB-CHMICA and detection in human urine samples.
abstract: Among the recently emerged synthetic cannabinoids, MDMB-CHMICA (methyl N-{[1-(cyclohexylmethyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate) shows an extraordinarily high prevalence in intoxication cases, necessitating analytical methods capable of detecting drug uptake. In this study, the in vivo phase I metabolism of MDMB-CHMICA was investigated using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry (LC-ESI-Q ToF-MS) techniques. The main metabolites are formed by hydrolysis of the methyl ester and oxidation of the cyclohexyl methyl side chain. One monohydroxylated metabolite, the ester hydrolysis product and two further hydroxylated metabolites of the ester hydrolysis product are suggested as suitable targets for a selective and sensitive detection in urine. All detected in vivo metabolites could be verified in vitro using a human liver microsome assay. Two of the postulated main metabolites were successfully included in a comprehensive LC-ESI-MS/MS screening method for synthetic cannabinoid metabolites. The screening of 5717 authentic urine samples resulted in 818 cases of confirmed MDMB-CHMICA consumption (14%). Since the most common route of administration is smoking, smoke condensates were analyzed to identify relevant thermal degradation products. Pyrolytic cleavage of the methyl ester and amide bond led to degradation products which were also formed metabolically. This is particularly important in hair analysis, where detection of metabolites is commonly considered a proof of consumption. In addition, intrinsic activity of MDMB-CHMICA at the CB1receptor was determined applying a cAMP accumulation assay and showed that the compound is a potent full agonist. Based on the collected data, an enhanced interpretation of analytical findings in urine and hair is facilitated. Copyright © 2016 John Wiley & Sons, Ltd.
authors: Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, 79104, Freiburg, Germany.|Hermann Staudinger Graduate School, University of Freiburg, Hebelstraße 27, 79104, Freiburg, Germany.
authors: Florian
authors: F
authors: Franz
authors: Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, 79104, Freiburg, Germany.|Hermann Staudinger Graduate School, University of Freiburg, Hebelstraße 27, 79104, Freiburg, Germany.
authors: Verena
authors: V
authors: Angerer
authors: Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, 79104, Freiburg, Germany.
authors: Bjoern
authors: B
authors: Moosmann
authors: Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Albertstr. 9, 79104, Freiburg, Germany.
authors: Volker
authors: V
authors: Auwärter
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D013287:Illicit Drugs / Q000378:metabolism* / Q000652:urine*; D007211:Indoles / Q000378:metabolism* / Q000652:urine*; D008862:Microsomes, Liver / Q000378:metabolism; D011619:Psychotropic Drugs / Q000378:metabolism / Q000652:urine; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D015813:Substance Abuse Detection / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D013287:Illicit Drugs; D007211:Indoles; D011619:Psychotropic Drugs; C000610109:methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate; D000242:Cyclic AMP
keywords: ADB-CHMICA; BB-22; LC-MS/MS; MMB-CHMINACA; new psychoactive substances