Abstract
Synthetic cathinones belong to the most often seized new psychoactive substances on an international level. This study investigated the toxicometabolomics, particularly the in vitro metabolism of 2-(methylamino)-1-(4-methylphenyl)-1-pentanone (4-MPD) and 2-(ethylamino)-1-(4-methylphenyl)-1-pentanone (4-MEAP) in pooled human liver microsomes (pHLM) using untargeted metabolomics techniques. Incubations were performed with the substrates in concentrations ranging from 0, 12.5, and 25 µM. Analysis was done by means of high-performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS/MS) in full scan only and the obtained data was evaluated using XCMS Online and MetaboAnalyst. Significant features were putatively identified using a separate parallel reaction monitoring method. Statistical analysis was performed using Kruskal-Wallis test for prefiltering significant features and subsequent hierarchical clustering, as well as principal component analysis (PCA). Hierarchical clustering or PCA showed a distinct clustering of all concentrations with most of the features z-scores rising with the concentration of the investigated substances. Identification of significant features left many of them unidentified but revealed metabolites of both 4-MPD and 4-MEAP. Both substances formed carboxylic acids, were hydroxylated at the alkyl chain, and formed metabolites after combined hydroxylation and reduction of the cathinone oxo group. 4-MPD additionally formed a dihydroxy metabolite and a hydroxylamine. 4-MEAP was additionally found reduced at the cathinone oxo group, N-dealkylated, and formed an oxo metabolite. These findings are the first to describe the metabolic pathways of 4-MPD and to extend our knowledge about the metabolism of 4-MEAP. Findings, particularly the MS data of the metabolites, are essential for setting up metabolite-based toxicological (urine) screening procedures.
Highlights
Synthetic cathinones, derived from naturally occurring alkaloids of Catha edulis (Vahl) Forssk. ex Endl., are one of the biggest groups of new psychoactive substances (NPS)
Besides their often-unknown pharmacological potency, a widely occurring problem is the false declaration of NPS sold online. 2-(Methylamino)-1-(4-methylphenyl)-1-pentanone
It is notable that the features M144T764, M189T31, M245T360, and M663T634 after analysis using reversed phase chromatography and positive ionization mode (Figure 2D) have comparatively high z-scores in group QC
Summary
Synthetic cathinones, derived from naturally occurring alkaloids of Catha edulis (Vahl) Forssk. ex Endl., are one of the biggest groups of new psychoactive substances (NPS). As classified by Simmler et al [2], cathinones have a distinct but diverse pharmacology, which allow the deduction of structure–activity relationships on the one hand but leave an uncertainty about the pharmacology of new cathinones on the other hand. Besides their often-unknown pharmacological potency, a widely occurring problem is the false declaration of NPS sold online. DDiissttiinnccttpphhaarrmmaaccoollooggiiccaallddaattaahhaassnnoott yyeett bbeeeenn rreeppoorrtteedd ffoorr 44--MMPPDD aanndd 44--MMEEAAPP, ,bbuuttttwwoo ccaasseerreeppoorrtstsooffmmisiususesewwereerepupbulbislihsehdedfofro4r-4M-MEAEPA. Metabolites 2021, 11, 3 both substances was only achieved by subtle differences in intensity and peak position in the fingerprinting region. Due to the in-house synthesis of both compounds, the occurrence of highly similar structural isomers is highly unlikely
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