The AAPS Journal

, Volume 19, Issue 6, pp 1767–1778 | Cite as

Pharmacokinetics of Mephedrone and Its Metabolites in Human by LC-MS/MS

  • Eulàlia Olesti
  • Magí Farré
  • Esther Papaseit
  • Aristotelis Krotonoulas
  • Mitona Pujadas
  • Rafael de la Torre
  • Óscar J. Pozo
Research Article
  • 187 Downloads

Abstract

Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of mephedrone, nor-mephedrone, N-succinyl-nor-mephedrone, 1′-dihydro-mephedrone, and 4′-carboxy-mephedrone. The method was validated in human plasma and urine and in rat brain homogenates. Six healthy male subjects, recreational users of new psychoactive substances, ingested 150 mg of mephedrone within the context of a clinical trial. 4′-Carboxy-mephedrone, followed by nor-mephedrone, was the most abundant metabolites found in plasma. Dihydro-mephedrone represented 10% of the amount of mephedrone in plasma and N-succinyl-nor-mephedrone was the metabolite eliminated with the longer half-life of 8.2 h. In urine, 4′-carboxy-mephedrone was the main metabolite excreted with amounts recovered being about 10 times those of mephedrone. Additionally, the validated method was used to test metabolite ability to cross the blood-brain barrier in vivo in rats with mephedrone and nor-mephedrone as the main active compounds present in the brain. The method described is useful for the determinations of mephedrone and metabolites in biological samples.

Graphical Abstract

KEY WORDS

analytical method LC-MS/MS mephedrone nor-mephedrone pharmacokinetics 

References

  1. 1.
    Brunt TM, Poortman A, Niesink RJ, van den Brink W. Instability of the ecstasy market and a new kid on the block: mephedrone. J Psychopharmacol. 2011;25(11):1543–7.CrossRefPubMedGoogle Scholar
  2. 2.
    European Monitoring Centre for Drugs and Drug Addiction. Report on the risk assessment of mephedrone in the framework of the Council Decision on new psychoactive substances. 2011. p.1–193.Google Scholar
  3. 3.
    United Nations Office on Drugs and Crime. World Drug Report. New York; 2016. p.1–174.Google Scholar
  4. 4.
    Busardò FP, Kyriakou C, Napoletano S, Marinelli E, Zaami S. Mephedrone related fatalities: a review. Eur Rev Med Pharmacol Sci. 2015;19(19):3777–90.PubMedGoogle Scholar
  5. 5.
    Pantano F, Tittarelli R, Mannocchi G, Pacifici R, Di Luca A, Paolo Busardò F, et al. Neurotoxicity induced by mephedrone: an up-to-date review. Curr Neuropharmacol. 2017;15(8):738–49.PubMedGoogle Scholar
  6. 6.
    Hong W, Ko Y, Lin M, Wang P, Chen Y, Chiueh L, et al. Determination of synthetic cathinones in urine using gas chromatography–mass spectrometry techniques. J Anal Toxicol. 2016;40(1):12–6.Google Scholar
  7. 7.
    Olesti E, Pujadas M, Papaseit E, Pérez-Mañá C, Pozo ÓJ, Farré M, et al. GC–MS quantification method for mephedrone in plasma and urine: application to human pharmacokinetics. J Anal Toxicol [Internet]. 2016;2–8. Available from: http://jat.oxfordjournals.org/lookup/doi/10.1093/jat/bkw120.
  8. 8.
    Torrance H, Cooper G. The detection of mephedrone (4-methylmethcathinone) in 4 fatalities in Scotland. Forensic Sci Int [Internet]. 2010;202(1–3):e62–3. doi:10.1016/j.forsciint.2010.07.014.
  9. 9.
    Mercolini L, Protti M, Catapano MC, Rudge J, Sberna AE LC-MS/MS and volumetric absorptive microsampling for quantitative bioanalysis of cathinone analogues in dried urine, plasma and oral fluid samples. J Pharm Biomed Anal. 2016;123:186–94.Google Scholar
  10. 10.
    Ambach L, Hernández Redondo A, König S, Weinmann W. Rapid and simple LC-MS/MS screening of 64 novel psychoactive substances using dried blood spots. Drug Test Anal. 2014;6(4):367–75.CrossRefPubMedGoogle Scholar
  11. 11.
    Amaratunga P, Lemberg BL, Lemberg D. Quantitative measurement of synthetic cathinones in oral fluid. J Anal Toxicol. 2013;37(9):622–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Shah SAB, NIK D, Barker J, Petróczi A, Cross P, Archer R, et al. Quantitative analysis of mephedrone using liquid chromatography tandem mass spectroscopy: application to human hair. J Pharm Biomed Anal. 2012;61:64–9.Google Scholar
  13. 13.
    Sørensen LK. Determination of cathinones and related ephedrines in forensic whole-blood samples by liquid-chromatography-electrospray tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879(11–12):727–36.CrossRefGoogle Scholar
  14. 14.
    Martínez-Clemente J, López-Arnau R, Carbó M, Pubill D, Camarasa J, Escubedo E. Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics. Psychopharmacology. 2013;229(2):295–306.CrossRefPubMedGoogle Scholar
  15. 15.
    Pozo ÓJ, Ibáñez M, Sancho JV, Lahoz-beneytez J, Farré M, Papaseit E, et al. Mass spectrometric evaluation of mephedrone in vivo human metabolism: identification of phase I and phase II metabolites, including a novel succinyl conjugate s. Drug Metab Dispos. 2014;43:248–57.CrossRefPubMedGoogle Scholar
  16. 16.
    Pedersen AJ, Reitzel LA, Johansen SS, Linnet K. In vitro metabolism studies on mephedrone and analysis of forensic cases. Drug Test Anal. 2013;5(6):430–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Khreit OIG, Grant MH, Zhang T, Henderson C, Watson DG, Sutcliffe OB. Elucidation of the phase I and phase II metabolic pathways of (±)-4′-methylmethcathinone (4-MMC) and (±)-4′-(trifluoromethyl)methcathinone (4-TFMMC) in rat liver hepatocytes using LC-MS and LC-MS2. J Pharm Biomed Anal. 2013;72:177–85.Google Scholar
  18. 18.
    Meyer MR, Wilhelm J, Peters FT, Maurer HH. Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry. Anal Bioanal Chem. 2010;397(3):1225–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Linhart I, Himl M, Židková M, Balíková M, Lhotková E, Páleníček T. Metabolic profile of mephedrone: identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites. Toxicol Lett. 2016;240(1):114–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Critical Review Report of Mephedrone. Expert Committe on Drug Dependence, World Health Organisation. 2014.Google Scholar
  21. 21.
    Papaseit E, Pérez-Mañá C, Mateus J-A, Pujadas M, Fonseca F, Torrens M, et al. Human pharmacology of mephedrone in comparison to MDMA. Neuropsychopharmacology. 2016;41(11):2704–13.Google Scholar
  22. 22.
    Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt N, Mihovilovic MD, et al. Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Br J Pharmacol. 2016;173(17):2657–68.Google Scholar
  23. 23.
    Martínez-Clemente J, Escubedo E, Pubill D, Camarasa J. Interaction of mephedrone with dopamine and serotonin targets in rats. Eur Neuropsychopharmacol. 2012;22(3):231–6.Google Scholar
  24. 24.
    Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE. Inhibition of plasma membrane monoamine transporters by β-ketoamphetamines. Eur J Pharmacol. 1999;381(1):63–9.CrossRefPubMedGoogle Scholar
  25. 25.
    European Medicines Agency. Guideline on bioanalytical method validation. EMA Guidel [Internet]. 2012;44(July 2011):1–23. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500109686&mid=WC0b01ac058009a3dc Google Scholar
  26. 26.
    Deventer K, Pozo OJ, Verstraete AG, Van Eenoo P. Dilute-and-shoot-liquid chromatography-mass spectrometry for urine analysis in doping control and analytical toxicology. TrAC - Trends Anal Chem. 2014;55:1–13.Google Scholar
  27. 27.
    de la Torre R, Farré M, Roset PN, Hernández-López C, Mas M, Ortuño J, et al. Pharmacology of MDMA in humans. Ann N Y Acad Sci. 2000;914:225–37.CrossRefPubMedGoogle Scholar
  28. 28.
    de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, et al. Human pharmacology of MDMA. Ther Drug Monit [Internet]. 2004;26(2):137–44.Google Scholar
  29. 29.
    Cruickshank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine. Addiction. 2009;104(7):1085–99.CrossRefPubMedGoogle Scholar
  30. 30.
    Toennes SW, Harder S, Schramm M, Niess C, Kauert GF. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br J Clin Pharmacol. 2003;56(1):125–30.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wu D, Victoria Otton S, Inaba T, Kalow W, Sellers EM. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol. 1997;53(11):1605–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Shimshoni JA, Britzi M, Sobol E, Willenz U, Nutt D, Edery N. 3-Methyl-methcathinone: pharmacokinetic profile evaluation in pigs in relation to pharmacodynamics. J Psychopharmacol. 2015;29(6):734–43.CrossRefPubMedGoogle Scholar
  33. 33.
    Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology [Internet]. 2012;37(5):1192–203. Nature Publishing Group; Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3306880&tool=pmcentrez&rendertype=abstract CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research ProgramIMIM (Hospital del Mar Medical Research Institute)BarcelonaSpain
  2. 2.Pompeu Fabra University (CEXS-UPF)BarcelonaSpain
  3. 3.Department of Clinical PharmacologyHospital Universitari Germans Trias i Pujol (IGTP)BadalonaSpain
  4. 4.School of MedicineUniversitat Autònoma de BarcelonaCerdanyola del VallèsSpain
  5. 5.Department of Biological Chemistry and Molecular ModellingInstitute of Advanced Chemistry of Catalonia, Spanish Council for Scientific Research (IQAC-CSIC)BarcelonaSpain
  6. 6.CIBER de Fisiopatología de la Obesidad y Nutrición (CB06/03), CIBEROBNMadridSpain

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