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
Deutscher übersetzter Titel: | Toxikokinetik neuer psychoaktiver Substanzen : Plasmaproteinbindung, metabolische Stabilität und Phase-I-Metabolismus des synthetischen Cannabinoids WIN 55,212-2, analysiert durch in-vitro-Methoden und LC-HR-MS/MS |
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Autor: | Mardal, Marie; Gracia-Lor, Emma; Leibnitz, Svenja; Castiglioni, Sara; Meyer, Markus R. |
Erschienen in: | Drug testing and analysis |
Veröffentlicht: | 8 (2016), 9/10, S. 1039-1048, Lit. |
Format: | Literatur (SPOLIT) |
Publikationstyp: | Zeitschriftenartikel |
Medienart: | Elektronische Ressource (online) Gedruckte Ressource |
Sprache: | Englisch |
ISSN: | 1942-7603, 1942-7611 |
DOI: | 10.1002/dta.1938 |
Schlagworte: | |
Online Zugang: | |
Erfassungsnummer: | PU201611008026 |
Quelle: | BISp |
Abstract des Autors
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.