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

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.

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Acknowledgements

This research has been funded by the European Commission (Drug Policy Initiatives, Justice Programme 2014-2020, contract no. HOME/2014/JDRU/AG/DRUG/7082, Predicting Risk of Emerging Drugs with In silico and Clinical Toxicology) and grants from the Instituto de Salud Carlos III FEDER (ISCII PI11/01961 and Red de Trastornos Adictivos RTA RD16/0017/003 and RD16/0017/0010). Other funding resources were the DIUE of the Generalitat de Catalunya (2014 SGR 680). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of the Instituto de Salud Carlos III, Madrid, Spain.

E.Papaseit was supported by a Juan Rodes fellowship (ISC-III, JR16/00020) and O.J. Pozo was funded by the Spanish Health National System (MS10/00576).

The authors would like to acknowledge the Clinical Research Unit of IMIM. We are also grateful to Cristina Fernández and Patricia Robledo for their collaboration in the animal experiments.

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Correspondence to Rafael de la Torre or Óscar J. Pozo.

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Olesti, E., Farré, M., Papaseit, E. et al. Pharmacokinetics of Mephedrone and Its Metabolites in Human by LC-MS/MS. AAPS J 19, 1767–1778 (2017). https://doi.org/10.1208/s12248-017-0132-2

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KEY WORDS

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