The online version of this article (https://doi.org/10.1007/s11419-018-0447-4) contains supplementary material, which is available to authorized users.
5F-CUMYL-PEGACLONE is a recently emerged γ-carbolinone derived synthetic cannabinoid. The present study aimed to identify phase I metabolites to reliably prove consumption of the substance by urine analysis and to differentiate from the uptake of the non-fluorinated analog CUMYL-PEGACLONE.
For metabolite characterization, phase I metabolites were analyzed by liquid chromatography–high resolution mass spectrometry after incubation with pooled human liver microsomes. Reliability of the biomarkers was evaluated by analysis of human urine samples (n = 20) by liquid chromatography–triple quadrupole tandem mass spectrometry. Sample preparation included β-glucuronidase treatment followed by liquid-liquid extraction.
In total, 15 metabolites were detected in vivo and characterized. Metabolic reactions were primarily observed at the γ-carbolinone core and the 5-fluoropentyl chain, and included N-dealkylation, hydroxylation, hydrolytic defluorination, formation of a dihydrodiol, oxidation to the pentanoic acid metabolite and formation of the propionic acid metabolite. Six of these metabolites were identical with phase I metabolites of CUMYL-PEGACLONE, which must be considered for interpretation of analytical findings in urine samples.
5F-CUMYL-PEGACLONE was subject to extensive metabolism in humans. The propionic acid metabolite was the most abundant metabolite in all urine samples and should be targeted when maximum sensitivity is needed (e.g., drug abstinence control). However, this metabolite also occurs in the biotransformation of the non-fluorinated analog and is, therefore, not a compound-specific marker. For differentiation, a metabolite hydroxylated at the γ-carbolinone core showed to be the most reliable marker and should be used as an additional target analyte.
Supplementary material 1 (DOCX 1094 kb)11419_2018_447_MOESM1_ESM.docx
EMCDDA (2018) European drug report 2018: trends and developments. Publications Office of the European Union, Luxembourg. https://doi.org/10.2810/800331
Huffman JW, Dai D, Martin BR, Compton DR (1994) Design, synthesis and pharmacology of cannabimimetic indoles. Bioorg Med Chem Lett 4:563–566. https://doi.org/10.1016/S0960-894x(01)80155-4 CrossRef
Buchler IP, Hayes MJ, Hegde SG, Hockerman SL, Jones DE, Kortum SW, Rico JG, Tenbrink RE,Wu KK (2009) Indazole derivatives. Patent WO2009/106982
Bowden MJ, Williamson JPB (2014) Cannabinoid compounds. Patent WO2014167530 A1
Longworth M, Banister SD, Boyd R, Kevin RC, Connor M, McGregor IS, Kassiou M (2017) Pharmacology of cumyl-carboxamide synthetic cannabinoid new psychoactive substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and their analogues. ACS Chem Neurosci 8:2159–2167. https://doi.org/10.1021/acschemneuro.7b00267 CrossRef
Angerer V, Mogler L, Steitz JP, Bisel P, Hess C, Schoeder CT, Müller CE, Huppertz LM, Westphal F, Schäper J, Auwärter V (2018) Structural characterization and pharmacological evaluation of the new synthetic cannabinoid CUMYL-PEGACLONE. Drug Test Anal 10:597–603. https://doi.org/10.1002/dta.2237 CrossRef
Ernst L, Brandhorst K, Papke U, Altrogge A, Zodel S, Langer N, Beuerle T (2017) Identification and quantification of synthetic cannabinoids in ‘spice-like’ herbal mixtures: update of the German situation in early 2017. Forensic Sci Int 277:51–58. https://doi.org/10.1016/j.forsciint.2017.05.019 CrossRef
Mogler L, Franz F, Wilde M, Huppertz LM, Halter S, Angerer V, Moosmann B, Auwärter V (2018) Phase I metabolism of the carbazole-derived synthetic cannabinoids EG-018, EG-2201, and MDMB-CHMCZCA and detection in human urine samples. Drug Test Anal. https://doi.org/10.1002/dta.2398
Carlier J, Diao X, Scheidweiler KB, Huestis MA (2017) Distinguishing intake of new synthetic cannabinoids ADB-PINACA and 5F-ADB-PINACA with human hepatocyte metabolites and high-resolution mass spectrometry. Clin Chem 63:1008–1021. https://doi.org/10.1373/clinchem.2016.267575 CrossRef
Mogler L, Franz F, Rentsch D, Angerer V, Weinfurtner G, Longworth M, Banister SD, Kassiou M, Moosmann B, Auwärter V (2018) Detection of the recently emerged synthetic cannabinoid 5F-MDMB-PICA in ‘legal high’ products and human urine samples. Drug Test Anal 10:196–205. https://doi.org/10.1002/dta.2201 CrossRef
Watanabe S, Kuzhiumparambil U, Winiarski Z, Fu S (2016) Biotransformation of synthetic cannabinoids JWH-018, JWH-073 and AM2201 by Cunninghamella elegans. Forensic Sci Int 261:33–42. https://doi.org/10.1016/j.forsciint.2015.12.023 CrossRef
Mußhoff F, Skopp G, Pragst F, Sachs H, Thieme D (2009) Guidelines for quality assurance in forensic-toxicological analyses. Toxichem Krimtech 76:142–176 (in German)
Kevin RC, Lefever TW, Snyder RW, Patel PR, Fennell TR, Wiley JL, McGregor IS, Thomas BF (2017) In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA. Forensic Toxicol 35:333–347. https://doi.org/10.1007/s11419-017-0361-1 CrossRefPubMedCentral
Shevyrin V, Melkozerov V, Nevero A, Eltsov O, Shafran Y, Morzherin Y, Lebedev AT (2015) Identification and analytical characteristics of synthetic cannabinoids with an indazole-3-carboxamide structure bearing a N-1-methoxycarbonylalkyl group. Anal Bioanal Chem 407:6301–6315. https://doi.org/10.1007/s00216-015-8612-7 CrossRef
Wohlfarth A, Gandhi AS, Pang S, Zhu M, Scheidweiler KB, Huestis MA (2014) Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry. Anal Bioanal Chem 406:1763–1780. https://doi.org/10.1007/s00216-014-7668-0 CrossRef
Diao X, Wohlfarth A, Pang S, Scheidweiler KB, Huestis MA (2016) High-resolution mass spectrometry for characterizing the metabolism of synthetic cannabinoid THJ-018 and its 5-fluoro analog THJ-2201 after incubation in human hepatocytes. Clin Chem 62:157–169. https://doi.org/10.1373/clinchem.2015.243535 CrossRef
- Human phase I metabolism of the novel synthetic cannabinoid 5F-CUMYL-PEGACLONE
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