Advertisement

Analytical and Bioanalytical Chemistry

, Volume 407, Issue 12, pp 3457–3470 | Cite as

Metabolic fate, mass spectral fragmentation, detectability, and differentiation in urine of the benzofuran designer drugs 6-APB and 6-MAPB in comparison to their 5-isomers using GC-MS and LC-(HR)-MSn techniques

  • Jessica Welter
  • Simon D. Brandt
  • Pierce Kavanagh
  • Markus R. Meyer
  • Hans H. MaurerEmail author
Research Paper

Abstract

The number of so-called new psychoactive substances (NPS) is still increasing by modification of the chemical structure of known (scheduled) drugs. As analogues of amphetamines, 2-aminopropyl-benzofurans were sold. They were consumed because of their euphoric and empathogenic effects. After the 5-(2-aminopropyl)benzofurans, the 6-(2-aminopropyl)benzofuran isomers appeared. Thus, the question arose whether the metabolic fate, the mass spectral fragmentation, and the detectability in urine are comparable or different and how an intake can be differentiated. In the present study, 6-(2-aminopropyl)benzofuran (6-APB) and its N-methyl derivative 6-MAPB (N-methyl-6-(2-aminopropyl)benzofuran) were investigated to answer these questions. The metabolites of both drugs were identified in rat urine and human liver preparations using GC-MS and/or liquid chromatography-high resolution-mass spectrometry (LC-HR-MSn). Besides the parent drug, the main metabolite of 6-APB was 4-carboxymethyl-3-hydroxy amphetamine and the main metabolites of 6-MAPB were 6-APB (N-demethyl metabolite) and 4-carboxymethyl-3-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 6-MAPB N-demethylation were CYP1A2, CYP2D6, and CYP3A4. An intake of a common users’ dose of 6-APB or 6-MAPB could be confirmed in rat urine using the authors’ GC-MS and the LC-MSn standard urine screening approaches with the corresponding parent drugs as major target allowing their differentiation. Furthermore, a differentiation of 6-APB and 6-MAPB in urine from their positional isomers 5-APB and 5-MAPB was successfully performed after solid phase extraction and heptafluorobutyrylation by GC-MS via their retention times.

Keywords

Designer drugs 6-APB 6-MAPB Metabolism GC-MS LC-(HR)-MSn 

Notes

Acknowledgments

The authors like to thank Achim Caspar, Julia Dinger, Andreas Helfer, Julian Michely, Carina Wink, Gabriele Ulrich, Carsten Schröder, and Armin A. Weber for the support and/or helpful discussion.

References

  1. 1.
    European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2014) European Drug Report: Trends and developments. http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf
  2. 2.
    Welter J, Kavanagh P, Meyer MR, Maurer HH (2015) Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques. Anal Bioanal Chem. doi: 10.1007/s00216-014-8360-0 Google Scholar
  3. 3.
    Advisory Council on the Misuse of Drugs (ACMD) (2013) Benzofurans: A review of the evidence of use and harm. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/261783/Benzofuran_compounds_report.pdf
  4. 4.
    Chan WL, Wood DM, Hudson S, Dargan PI (2013) Acute psychosis associated with recreational use of benzofuran 6-(2-aminopropyl)benzofuran (6-APB) and cannabis. J Med Toxicol 9:278–281CrossRefGoogle Scholar
  5. 5.
    Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (2013) Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol 700:147–151CrossRefGoogle Scholar
  6. 6.
    Stanczuk A, Morris N, Gardner EA, Kavanagh P (2013) Identification of (2-aminopropyl)benzofuran (APB) phenyl ring positional isomers in internet purchased products. Drug Test Anal 5:270–276CrossRefGoogle Scholar
  7. 7.
    Casale JF, Hays PA (2012) The characterization of 6-(2-aminopropyl)benzofuran and differentiation from its 4-, 5-, and 7-positional analogues. Microgram J 9:61–74Google Scholar
  8. 8.
    Welter J, Meyer MR, Wolf E, Weinmann W, Kavanagh P, Maurer HH (2013) 2-Methiopropamine, a thiophene analogue of methamphetamine: studies on its metabolism and detectability in the rat and human using GC-MS and LC-(HR)-MS techniques. Anal Bioanal Chem 405:3125–3135CrossRefGoogle Scholar
  9. 9.
    Maurer HH, Pfleger K, Weber AA (2011) Mass spectral and GC data of drugs, poisons, pesticides, pollutants and their metabolites. Wiley-VCH, Weinheim (Germany)Google Scholar
  10. 10.
    Ewald AH, Ehlers D, Maurer HH (2008) Metabolism and toxicological detection of the designer drug 4-chloro-2,5-dimethoxyamphetamine in rat urine using gas chromatography-mass spectrometry. Anal Bioanal Chem 390:1837–1842CrossRefGoogle Scholar
  11. 11.
    Meyer MR, Peters FT, Maurer HH (2010) Automated mass spectral deconvolution and identification system for GC-MS screening for drugs, poisons, and metabolites in urine. Clin Chem 56:575–584CrossRefGoogle Scholar
  12. 12.
    Wissenbach DK, Meyer MR, Remane D, Weber AA, Maurer HH (2011) Development of the first metabolite-based LC-MSn urine drug screening procedure—exemplified for antidepressants. Anal Bioanal Chem 400:79–88CrossRefGoogle Scholar
  13. 13.
    Peters FT, Schaefer S, Staack RF, Kraemer T, Maurer HH (2003) Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry. J Mass Spectrom 38:659–676CrossRefGoogle Scholar
  14. 14.
    Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157:907–921CrossRefGoogle Scholar
  15. 15.
    Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O’Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269–299CrossRefGoogle Scholar
  16. 16.
    Meyer MR, Vollmar C, Schwaninger AE, Maurer HH (2012) New cathinone-derived designer drugs 3-bromomethcathinone and 3-fluoromethcathinone: studies on their metabolism in rat urine and human liver microsomes using GC-MS and LC-high-resolution MS and their detectability in urine. J Mass Spectrom 47:253–262CrossRefGoogle Scholar
  17. 17.
    Connelly JC, Connor SC, Monte S, Bailey NJ, Borgeaud N, Holmes E, Troke J, Nicholson JK, Gavaghan CL (2002) Application of directly coupled high performance liquid chromatography-NMR-mass spectometry and 1H NMR spectroscopic studies to the investigation of 2,3-benzofuran metabolism in Sprague-Dawley rats. Drug Metab Dispos 30:1357–1363CrossRefGoogle Scholar
  18. 18.
    Kobayashi T, Sugihara J, Harigaya S (1987) Mechanism of metabolic cleavage of a furan ring. Drug Metab Dispos 15:877–881Google Scholar
  19. 19.
    Le Fur JM, Labaune JP (1985) Metabolic pathway by cleavage of a furan ring. Xenobiotica 15:567–577CrossRefGoogle Scholar
  20. 20.
    Renzulli C, Nash M, Wright M, Thomas S, Zamuner S, Pellegatti M, Bettica P, Boyle G (2011) Disposition and metabolism of [14C]SB-649868, an orexin 1 and 2 receptor antagonist, in humans. Drug Metab Dispos 39:215–227CrossRefGoogle Scholar
  21. 21.
    Ravindranath V, Burka LT, Boyd MR (1984) Reactive metabolites from the bioactivation of toxic methylfurans. Science 224:884–886CrossRefGoogle Scholar
  22. 22.
    Ou T, Tatsumi K, Yoshimura H (1977) Isolation and identification of urinary metabolites of AF-2 (3-(5-nitro-2-furyl)-2-(2-furyl)acrylamide) in rabbits. Biochem Biophys Res Commun 75:401–405CrossRefGoogle Scholar
  23. 23.
    McLafferty FW, Turecek F (1993) Interpretation of Mass Spectra. University Science Books, Mill ValleyGoogle Scholar
  24. 24.
    Smith RM, Busch KL (1999) Understanding mass spectra—a basic approach. Wiley, New YorkGoogle Scholar
  25. 25.
    Helfer AG, Turcant A, Boels D, Ferec S, Lelievre B, Welter J, Meyer MR, Maurer HH (2014) Elucidation of the metabolites of the novel psychoactive substance 4-methyl-N-ethyl-cathinone (4-MEC) in human urine and pooled liver microsomes by GC-MS and LC-HR-MS/MS techniques and of its detectability by GC-MS or LC-MSn standard screening approaches. Drug Test Anal. doi: 10.1002/dta.1682 Google Scholar
  26. 26.
    Dinger J, Meyer MR, Maurer HH (2014) In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two cocktail approach. Arch Toxicol. doi: 10.1007/s00204-014-1412-6 Google Scholar
  27. 27.
    Wissenbach DK, Meyer MR, Remane D, Philipp AA, Weber AA, Maurer HH (2011) Drugs of abuse screening in urine as part of a metabolite-based LC-MS(n) screening concept. Anal Bioanal Chem 400:3481–3489CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jessica Welter
    • 1
  • Simon D. Brandt
    • 2
  • Pierce Kavanagh
    • 3
  • Markus R. Meyer
    • 1
  • Hans H. Maurer
    • 1
    Email author
  1. 1.Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and ToxicologySaarland UniversityHomburgGermany
  2. 2.School of Pharmacy & Biomolecular SciencesLiverpool John Moores UniversityLiverpoolUK
  3. 3.Department of Pharmacology and Therapeutics, Trinity Centre for Health and SciencesSt. James’s HospitalDublin 8Ireland

Personalised recommendations