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Forensic Toxicology
Published in: Forensic Toxicology 2/2017

01-07-2017 | Original Article

In vitro metabolism of new synthetic cannabinoid SDB-006 in human hepatocytes by high-resolution mass spectrometry

Authors: Xingxing Diao, Jeremy Carlier, Karl B. Scheidweiler, Marilyn A. Huestis

Published in: Forensic Toxicology | Issue 2/2017

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Abstract

The drug abuse epidemic within the United States remains one of the nation’s most serious social challenges, especially among adolescents and young adults. Novel psychoactive substances continuously emerge into the illicit drugs-of-abuse market to evade legislation. In 2013, SDB-006 was detected as a novel synthetic cannabinoid (SC) with high binding affinity to CB1 (EC50 = 19 nM) and CB2 (EC50 = 134 nM). Unfortunately, no human metabolism data for SDB-006 are currently available, making it challenging to confirm intake, since all previously investigated SCs were extensively metabolized. The present study aims to recommend appropriate marker metabolites for documenting SDB-006 consumption by investigating its metabolism in human hepatocytes. For metabolite profiling, 10 µM of SDB-006 was incubated in human hepatocytes for 3 h. Metabolite identification in hepatocyte samples was accomplished with high-resolution mass spectrometry via information-dependent data acquisition. Results revealed that SDB-006 was highly metabolized in human hepatocytes. A total of 20 metabolites were characterized, generated mainly from hydroxylation and glucuronidation. Hydroxylation occurred primarily on several positions of the pentyl chain. N-Dealkylation was the other major pathway, including depentylation and debenzylation. Based on our data, we propose 4′-keto-SDB-006 (M19) and pentyl-OH-SDB-006 (M15) as optimal marker metabolites for documenting SDB-006 intake.
Literature
1.
Auwärter V, Dresen S, Weinmann W, Müller M, Putz M, Ferreirós N (2009) ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom 44:832–837CrossRefPubMed
2.
Namera A, Kawamura M, Nakamoto A, Saito T, Nagao M (2015) Comprehensive review of the detection methods for synthetic cannabinoids and cathinones. Forensic Toxicol 33:175–194CrossRefPubMedPubMedCentral
3.
4.
Huffman JW, Dai D, Martin BR, Compton DR (1994) Design, synthesis and pharmacology of cannabimimetic indoles. Bioorg Med Chem Lett 4:563–566CrossRef
5.
6.
Scheidweiler KB, Jarvis MJ, Huestis MA (2015) Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry. Anal Bioanal Chem 407:883–897CrossRefPubMed
7.
8.
Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2013) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108:534–544CrossRefPubMed
9.
Seely KA, Lapoint J, Moran JH, Fattore L (2012) Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 39:234–243CrossRefPubMedPubMedCentral
10.
Forrester MB, Kleinschmidt K, Schwarz E, Young A (2012) Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 31:1006–1011CrossRefPubMed
11.
Young AC, Schwarz E, Medina G, Obafemi A, Feng S-Y, Kane C, Kleinschmidt K (2012) Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med 30:1320.e5–1320.e7CrossRef
12.
Wohlfarth A, Roman M, Andersson M, Kugelberg FC, Diao X, Carlier J, Eriksson C, Wu X, Konradsson P, Josefsson M, Huestis MA, Kronstrand R (2016) 25C-NBOMe and 25I-NBOMe metabolite studies in human hepatocytes, in vivo mouse and human urine with high-resolution mass spectrometry. Drug Test Anal. doi:10.​1002/​dta.​2044
13.
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 62:157–169CrossRefPubMed
14.
Kemp AM, Clark MS, Dobbs T, Galli R, Sherman J, Cox R (2016) Top 10 facts you need to know about synthetic cannabinoids: not so nice spice. Am J Med 129:240.e1–244.e1CrossRef
15.
Law R, Schier J, Martin C, Chang A, Wolkin A (2015) Notes from the field: increase in reported adverse health effects related to synthetic cannabinoid use–United States, January–May 2015. Morb Mortal Wkly Rep 64:618–619
16.
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 406:1763–1780CrossRefPubMed
17.
Uchiyama N, Asakawa K, Kikura-Hanajiri R, Tsutsumi T, Hakamatsuka T (2015) A new pyrazole-carboxamide type synthetic cannabinoid AB-CHFUPYCA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide] identified in illegal products. Forensic Toxicol 33:367–373CrossRef
18.
Diao X, Scheidweiler KB, Wohlfarth A, Zhu M, Pang S, Huestis MA (2016) Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes. Forensic Toxicol 34:256–267CrossRefPubMedPubMedCentral
19.
Shevyrin V, Melkozerov V, Nevero A, Eltsov O, Baranovsky A, Shafran Y (2014) Synthetic cannabinoids as designer drugs: new representatives of indol-3-carboxylates series and indazole-3-carboxylates as novel group of cannabinoids. Identification and analytical data. Forensic Sci Int 244:263–275CrossRefPubMed
20.
Castaneto MS, Wohlfarth A, Pang S, Zhu M, Scheidweiler KB, Kronstrand R, Huestis MA (2015) Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry. Forensic Toxicol 33:295–310CrossRef
21.
Wohlfarth A, Castaneto MS, Zhu M, Pang S, Scheidweiler KB, Kronstrand R, Huestis MA (2015) Pentylindole/pentylindazole synthetic cannabinoids and their 5-fluoro analogs produce different primary metabolites: metabolite profiling for AB-PINACA and 5F-AB-PINACA. AAPS J 17:660–677CrossRefPubMedPubMedCentral
22.
Swortwood MJ, Carlier J, Ellefsen KN, Wohlfarth A, Diao X, Concheiro-Guisan M, Kronstrand R, Huestis MA (2016) In vitro, in vivo and in silico metabolic profiling of α-pyrrolidinopentiothiophenone, a novel thiophene stimulant. Bioanalysis 8:65–82CrossRefPubMed
23.
Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH (2012) Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2184CrossRefPubMedPubMedCentral
24.
Sobolevsky T, Prasolov I, Rodchenkov G (2012) Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal 4:745–753CrossRefPubMed
25.
Tait RJ, Caldicott D, Mountain D, Hill SL, Lenton S (2016) A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clin Toxicol 54:1–13CrossRef
26.
Andersson M, Diao X, Wohlfarth A, Scheidweiler KB, Huestis MA (2016) Metabolic profiling of new synthetic cannabinoids AMB and 5F-AMB by human hepatocyte and liver microsome incubations and high-resolution mass spectrometry. Rapid Commun Mass Spectrom 30:1067–1078CrossRefPubMed
27.
Diao X, Pang X, Xie C, Guo Z, Zhong D, Chen X (2014) Bioactivation of 3-n-butylphthalide via sulfation of its major metabolite 3-hydroxy-NBP: mediated mainly by sulfotransferase 1A1. Drug Metab Dispos 42:774–781CrossRefPubMed
28.
Wilkinson SM, Banister SD, Kassiou M (2015) Bioisosteric fluorine in the clandestine design of synthetic cannabinoids. Aust J Chem 68:4–8CrossRef
29.
30.
Diao X, Scheidweiler KB, Wohlfarth A, Pang S, Kronstrand R, Huestis MA (2016) In vitro and in vivo human metabolism of synthetic cannabinoids FDU-PB-22 and FUB-PB-22. AAPS J 18:455–464CrossRefPubMedPubMedCentral
31.
Diao X, Carlier J, Zhu M, Pang S, Kronstrand R, Scheidweiler KB, Huestis MA (2017) In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201). Forensic Toxicol 35:20–32CrossRefPubMed
32.
Maurer HH, Meyer MR (2016) High-resolution mass spectrometry in toxicology: current status and future perspectives. Arch Toxicol 90:2161–2172CrossRefPubMed
33.
Zhu Y, Li L, Zhang G, Wan H, Yang C, Diao X, Chen X, Zhang L, Zhong D (2016) Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Chromatogr B 1033-1034:117–127CrossRef
34.
Kronstrand R, Brinkhagen L, Birath-Karlsson C, Roman M, Josefsson M (2014) LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine. Anal Bioanal Chem 406:3599–3609CrossRefPubMed
35.
Jiang J, Pang X, Li L, Dai X, Diao X, Chen X, Zhong D, Wang Y, Chen Y (2016) Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide. Drug Des Devel Ther 10:2181–2191CrossRefPubMedPubMedCentral
36.
Diao X, Deng P, Xie C, Li X, Zhong D, Zhang Y, Chen X (2013) Metabolism and pharmacokinetics of 3-n-butylphthalide (NBP) in humans: the role of cytochrome P450s and alcohol dehydrogenase in biotransformation. Drug Metab Dispos 41:430–444CrossRefPubMed
37.
Diao X, Ma Z, Wang H, Zhong D, Zhang Y, Jin J, Fan Y, Chen X (2013) Simultaneous quantitation of 3-n-butylphthalide (NBP) and its four major metabolites in human plasma by LC–MS/MS using deuterated internal standards. J Pharm Biomed Anal 78-79:19–26CrossRefPubMed
38.
Diao X, Huestis MA (2016) Approaches, challenges and advances in metabolism of new synthetic cannabinoids and identification of optimal urinary marker metabolites. Clin Pharmacol Ther. doi:10.​1002/​cpt.​1534 PubMed
Metadata
Title
In vitro metabolism of new synthetic cannabinoid SDB-006 in human hepatocytes by high-resolution mass spectrometry
Authors
Xingxing Diao
Jeremy Carlier
Karl B. Scheidweiler
Marilyn A. Huestis
Publication date
01-07-2017
Publisher
Springer Japan
Published in
Forensic Toxicology / Issue 2/2017
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI
https://doi.org/10.1007/s11419-016-0350-9

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