Study of the in vitro and in vivo metabolism of 4-HO-MET

Pia Simona Bruni; Katharina Elisabeth Grafinger; Susanne Nussbaumer; Stefan König; Stefan Schürch; Wolfgang Weinmann

doi:10.1016/j.forsciint.2018.06.037

Study of the in vitro and in vivo metabolism of 4-HO-MET

Forensic Sci Int. 2018 Sep:290:103-110. doi: 10.1016/j.forsciint.2018.06.037. Epub 2018 Jul 4.

Authors

Pia Simona Bruni¹, Katharina Elisabeth Grafinger², Susanne Nussbaumer³, Stefan König³, Stefan Schürch⁴, Wolfgang Weinmann⁵

Affiliations

¹ Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bühlstrasse 20, CH-3012 Bern, Switzerland; Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
² Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bühlstrasse 20, CH-3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
³ Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bühlstrasse 20, CH-3012 Bern, Switzerland.
⁴ Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
⁵ Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bühlstrasse 20, CH-3012 Bern, Switzerland. Electronic address: wolfgang.weinmann@irm.unibe.ch.

PMID: 30015274
DOI: 10.1016/j.forsciint.2018.06.037

Abstract

4-Hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET) is a new psychoactive substance (NPS) of the chemical class of tryptamines. It shows structural similarities to the endogenous neurotransmitter serotonin, and is a serotonergic hallucinogen, affecting emotional, motoric, and cognitive functions. The knowledge about its biotransformation is mandatory to confirm the abuse of the substance by urine analysis in forensic cases. Therefore, phase I metabolites were generated by the use of the pooled human liver microsomes (pHLM) in vitro model and analyzed by high-performance liquid chromatography high-resolution tandem mass spectrometry with information-dependent acquisition (HPLC-IDA-HR-MS/MS). Furthermore, three authentic urine samples was analyzed and results were compared: 12 different in vitro and 4 in vivo metabolites were found. The predominant biotransformation steps observed in vitro were mono- or dihydroxylation of 4-HO-MET, besides demethylation, demethylation in combination with monohydroxylation, formation of a carboxylic acid, deethylation, and oxidative deamination. In vivo, monohydroxylation, and glucuronidation were detected. A metabolic pathway based on these results was proposed. For the analysis of urine samples in forensic cases, the N-oxide metabolite and the HO-alkyl metabolite are recommended as target compounds, besides the glucuronides of 4-HO-MET and the parent compound 4-HO-MET itself.

Keywords: 4-HO-MET; HPLC-IDA-HR-MS/MS; Human liver microsomes; Metabolism; NPS; Synthetic tryptamine.

MeSH terms

Biotransformation
Chromatography, Liquid
Designer Drugs / pharmacokinetics*
Female
Forensic Toxicology
Humans
Male
Microsomes, Liver / chemistry
Psychotropic Drugs / pharmacokinetics*
Psychotropic Drugs / urine
Tandem Mass Spectrometry
Tryptamines / pharmacokinetics*
Tryptamines / urine

Substances

Designer Drugs
Psychotropic Drugs
Tryptamines