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Drug Test Anal. 2016 Oct;8(10):1039-1048. doi: 10.1002/dta.1938. Epub 2016 Jan 26.

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.

Author information

1
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421, Homburg, Saar, Germany.
2
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Department of Environmental Health Sciences, Via La Masa 19, 20156, Milan, Italy.
3
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421, Homburg, Saar, Germany. markus.meyer@ki.se.
4
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. markus.meyer@ki.se.

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.

KEYWORDS:

LC-HR-MS/MS; designer drugs; human liver microsomes; metabolic stability; synthetic cannabinoids

PMID:
26810883
DOI:
10.1002/dta.1938
[Indexed for MEDLINE]

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