Toxicokinetics of new psychoactive substances: Plasma protein binding, metabolic stability, and human phase I metabolism of the synthetic cannabinoid WIN 55,212-2 studied using in vitro tools and LC-HR-MS/MS

Marie Mardal, Emma Gracia-Lor, Svenja Leibnitz, Sara Castiglioni, Markus R. Meyer

Research output: Contribution to journalArticlepeer-review

Abstract

The new psychoactive substance WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone) is a potent synthetic cannabinoid receptor agonist. The metabolism of WIN 55,212-2 in man has never been reported. Therefore, the aim of this study was to identify the human in vitro metabolites of WIN 55,212-2 using pooled human liver microsomes and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) to provide targets for toxicological, doping, and environmental screening procedures. Moreover, a metabolic stability study in pooled human liver microsomes (pHLM) was carried out. In total, 19 metabolites were identified and the following partly overlapping metabolic steps were deduced: degradation of the morpholine ring via hydroxylation, N- and O-dealkylation, and oxidative deamination, hydroxylations on either the naphthalene or morpholine ring or the alkyl spacer with subsequent oxidation, epoxide formation with subsequent hydrolysis, or combinations. In conclusion, WIN 55,212-2 was extensively metabolized in human liver microsomes incubations and the calculated hepatic clearance was comparably high, indicating a fast and nearly complete metabolism in vivo. This is in line with previous findings on other synthetic cannabinoids.

Original languageEnglish
Pages (from-to)1039-1048
JournalDrug Testing and Analysis
Volume8
DOIs
Publication statusPublished - 2016

Keywords

  • Designer drugs
  • Human liver microsomes
  • LC-HR-MS/MS
  • Metabolic stability
  • Synthetic cannabinoids

ASJC Scopus subject areas

  • Analytical Chemistry
  • Environmental Chemistry
  • Pharmaceutical Science
  • Spectroscopy

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