Majed Alshamaileh
A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
Alshamaileh, Majed; Hussain, Issam; Baron, Mark; Croxton, Ruth; Vetter, Marleen; Gonzalez-Rodriguez, Jose
Authors
Issam Hussain
Mark Baron
Ruth Croxton
Marleen Vetter
Jose Gonzalez-Rodriguez
Abstract
In the current study, the metabolism of two novel psychoactive substances (NPSs), mephedrone and methoxetamine (MXE), was studied in vitro in pig liver microsomes to determine potential metabolites by liquid chromatography-mass spectrometry (LC-MS). Later, in vitro studies were performed using HepaRG™ cells to determine the human metabolites of these drugs using gas chromatography-mass spectrometry (GC-MS). The aim of the study was to detect metabolites from the metabolic mixture in the human cell lines using GC-MS, since this is a more readily available technique within forensic laboratories. Microsomes were prepared through a conventional ultracentrifugation method and incubated under optimized conditions with the drugs for 3 h. Subsequently, the samples were investigated using LC-MS. A similar methodology was then applied in the HepaRG™ cells, and the GC-MS conditions were optimized using N,O-bis(trimethylsilyl)trifluoroacetamide as a derivatization agent. The analysis showed two molecules from a successful in vitro metabolism, namely, hydroxytoly-mephedrone and nor-dihydro mephedrone. For MXE, two metabolites are presented produced by the O-demethylation and reduction of the ketone moiety to the corresponding alcohol, respectively. Using the human HepaRG™ cells, only nor-dihydro mephedrone could be identified by GC-MS. Since hydroxytoly-mephedrone and the MXE metabolites are more polar, it is suggested that GC-MS even with derivatization may not be suitable. In addition, cytotoxicity was studied utilizing HepaRG™ cell lines. The drugs show cytotoxic effects causing in vitro cell death, within the specified range of EC50 0.3211 mM (79 μg/mL) and 0.6297 mM (111 μg/mL) for mephedrone and MXE, respectively. These drugs were able to cause 73–84% cell death.
Citation
Alshamaileh, M., Hussain, I., Baron, M., Croxton, R., Vetter, M., & Gonzalez-Rodriguez, J. (2020). A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses. Open Chemistry, 18(1), 1507-1522. https://doi.org/10.1515/chem-2020-0184
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 16, 2020 |
Online Publication Date | Dec 23, 2020 |
Publication Date | 2020-01 |
Deposit Date | Jan 14, 2021 |
Publicly Available Date | Mar 28, 2024 |
Journal | Open Chemistry |
Print ISSN | 2391-5420 |
Publisher | De Gruyter Open |
Peer Reviewed | Peer Reviewed |
Volume | 18 |
Issue | 1 |
Pages | 1507-1522 |
DOI | https://doi.org/10.1515/chem-2020-0184 |
Keywords | In vitro metabolism; Mephedrone; Methoxetamine; Cytotoxicity; Mass spectrometry; EC50 |
Public URL | https://hull-repository.worktribe.com/output/3693025 |
Publisher URL | https://www.degruyter.com/view/journals/chem/18/1/article-p1507.xml?language=en |
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Copyright Statement
© 2020 Majed Alshamaileh et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. BY 4.0
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