Advertisement

Analytical and Bioanalytical Chemistry

, Volume 407, Issue 6, pp 1545–1557 | Cite as

Lefetamine, a controlled drug and pharmaceutical lead of new designer drugs: synthesis, metabolism, and detectability in urine and human liver preparations using GC-MS, LC-MSn, and LC-high resolution-MS/MS

  • Carina S. D. Wink
  • Golo M. J. Meyer
  • Josef Zapp
  • Hans H. Maurer
Paper in Forefront

Abstract

Lefetamine (N,N-dimethyl-1,2-diphenylethylamine, L-SPA) was marketed as an opioid analgesic in Japan and Italy. After being widely abused, it became a controlled substance. It seems to be a pharmaceutical lead for designer drugs because N-ethyl-1,2-diphenylethylamine (NEDPA) and N-iso-propyl-1,2-diphenylethylamine (NPDPA) were confiscated by the German police. In contrast to these derivatives, metabolism and detectability of lefetamine were not studied yet. Therefore, phase I and II metabolism should be elucidated and correlated to the derivatives. Also the detectability using the authors’ standard urine screening approaches (SUSA) needed to be checked. As lefetamine was commercially unavailable, it had to be synthesized first. For metabolism studies, a high dose of lefetamine was administered to rats and the urine samples worked up in different ways. Separation and analysis were achieved by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). In accordance with NEPDA and NPDPA, the following metabolic steps could be proposed: N-oxidation, N-dealkylation, mono- and bis-hydroxylation of the benzene ring, and hydroxylation of the phenyl ring only after N-dealkylation. The di-hydroxy metabolites were conjugated by methylation of one hydroxy group, and hydroxy metabolites by glucuronidation or sulfation. All initial metabolites could also be detected in human liver preparations. After a therapeutic lefetamine dose, the bis-nor, bis-nor-hydroxy, nor-hydroxy, nor-di-hydroxy metabolites could be detected using the authors’ GC-MS SUSA and the nor-hydroxy-glucuronide by the LC-MSn SUSA. Thus, an intake of lefetamine should be detectable in human urine assuming similar pharmacokinetics.

Keywords

Drugs of abuse Lefetamine Metabolism GC-MS LC-HR-MS/MS 

Notes

Acknowledgments

The authors thank Andreas Helfer, Markus Meyer, Julian Michely, Carsten Schröder, Christian Steuer, Gabriele Ulrich, and Armin A. Weber for their support and helpful discussions.

References

  1. 1.
    Expert Committee on Addiction-Producing Drugs (1961) Expert committee on addiction-producing drugs. Eleventh report. World Health Organ Tech Rep Ser 211:1–16Google Scholar
  2. 2.
    Paroli E, Nencini P, Moscucci M (1984) Clinical and experimental evidence of an opiate-like activity of lefetamine. Pharmacol Res Commun 16:915–922CrossRefGoogle Scholar
  3. 3.
    Janiri L, Mannelli P, Persico AM, Serretti A, Tempesta E (1994) Opiate detoxification of methadone maintenance patients using lefetamine, clonidine, and buprenorphine. Drug Alcohol Depend 36:139–145CrossRefGoogle Scholar
  4. 4.
    Mannelli P, Janiri L, De MM, Tempesta E (1989) Lefetamine: new abuse of an old drug—clinical evaluation of opioid activity. Drug Alcohol Depend 24:95–101CrossRefGoogle Scholar
  5. 5.
    De Montis MG, Devoto P, Bucarelli A, Tagliamonte A (1985) Opioid activity of lefetamine. Pharmacol Res Commun 17:471–478CrossRefGoogle Scholar
  6. 6.
    Janiri L, Persico AM, Tempesta E (1989) Dual effects of lephetamine on spontaneous and evoked neuronal firing in the somatosensory cortex of the rat. Neuropharmacology 28:1405–1410CrossRefGoogle Scholar
  7. 7.
    Westphal F, Junge T, Jacobsen-Bauer A, Rösner P (2010) Lefetamin-Derivate: alte Bekannte neu auf dem Drogenmarkt. Toxichem Krimtech 77:46–58Google Scholar
  8. 8.
    Wink CSD, Meyer GMJ, Wissenbach DK, Jacobsen-Bauer A, Meyer MR, Maurer HH (2014) Lefetamine-derived designer drugs N-ethyl-1,2-diphenylethylamine (NEDPA) and N-iso-propyl-1,2-diphenylethylamine (NPDPA): metabolism and detectability in rat urine using GC-MS, LC-MSn and LC-high resolution (HR)-MS/MS. Drug Test Anal 6:1038–1048CrossRefGoogle 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, WeinheimGoogle Scholar
  10. 10.
    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-MSn screening concept. Anal Bioanal Chem 400:3481–3489CrossRefGoogle Scholar
  11. 11.
    Maurer HH, Wissenbach DK, Weber AA (2014) Maurer/Wissenbach/Weber MWW LC-MSn library of drugs, poisons, and their metabolites. Wiley-VCH, WeinheimGoogle Scholar
  12. 12.
    Rosenau T, Potthast A, Rohrling J, Hofinger A, Sixta H, Kosma P (2002) A solvent-free and formalin-free Eschweiler-Clarke methylation for amines. Synth Commun 32:457–466CrossRefGoogle Scholar
  13. 13.
    Moore JL, Taylor SM, Soloshonok VA (2005) An efficient and operationally convenient general synthesis of tertiary amines by direct alkylation of secondary amines with alkyl halides in the presence of Huenig’s base. Arkivoc (Arch Organ Chem) 2005:287–292CrossRefGoogle Scholar
  14. 14.
    Malz F (2003) Quantitative NMR-Specktroskopie als Referenzverfahren in der alaytischen Chemie. PhD thesis, Humboldt-Universität Berlin, BerlinGoogle Scholar
  15. 15.
    Meyer GMJ, Wink CSD, Zapp J, Maurer HH (2015) GC-MS, LC-MSn, LC-high resolution-MSn, and NMR studies on the metabolism and toxicological detection of mesembrine and mesembrenone, the main alkaloids of the legal high “Kanna” isolated from Sceletium tortuosum. Anal Bioanal Chem. doi: 10.1007/s00216-014-8109-9 Google Scholar
  16. 16.
    Maurer HH, Pfleger K, Weber AA (2011) Mass spectral library of drugs, poisons, pesticides, pollutants, and their metabolites. Wiley-VCH, WeinheimGoogle Scholar
  17. 17.
    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
  18. 18.
    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
  19. 19.
    McLafferty FW, Turecek F (1993) Interpretation of mass spectra. University Science Books, Mill ValleyGoogle Scholar
  20. 20.
    Smith RM, Busch KL (1999) Understanding mass spectra—a basic approach. Wiley, New YorkGoogle Scholar
  21. 21.
    Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157:907–921CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Carina S. D. Wink
    • 1
  • Golo M. J. Meyer
    • 1
  • Josef Zapp
    • 2
  • Hans H. Maurer
    • 1
  1. 1.Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and ToxicologySaarland UniversityHomburgGermany
  2. 2.Department of Pharmaceutical BiologySaarland UniversitySaarbrückenGermany

Personalised recommendations