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Metabolic Profile of Four Selected Cathinones in Microsome Incubations: Identification of Phase I and II Metabolites by Liquid Chromatography High Resolution Mass Spectrometry

2021-01-12Artigo científico Acesso aberto
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datacite.subject.fosCiências Naturais::Ciências Químicas
datacite.subject.sdg12:Produção e Consumo Sustentáveis
datacite.subject.sdg13:Ação Climática
datacite.subject.sdg14:Proteger a Vida Marinha
dc.contributor.authorLopes, Beatriz T.
dc.contributor.authorCaldeira, Maria João
dc.contributor.authorGaspar, Helena
dc.contributor.authorAntunes, Alexandra M. M.
dc.date.accessioned2026-04-09T13:53:38Z
dc.date.available2026-04-09T13:53:38Z
dc.date.issued2021-01-12
dc.description.abstractConsumption of synthetic cathinones, the second largest class of new psychoactive substances (NPS) reported worldwide, represents a serious public health risk. One of the biggest challenges created by the rapid spread of NPS on the illegal drug market is the discovery of selective biomarkers for their detection in biological matrices, which is only possible through the study of their metabolic profile. The synthetic cathinones 4′-methyl-N,N-dimethylcathinone (4-MDMC), 4′-methyl-N,N-diethylcathinone (4-MDEC), 4′-chloro-α-pyrrolidinovalerophenone (4Cl-PVP), and 4′-chloroethylcathinone (4-CEC) are NPS recently seized in Europe, and, with the exception of 4-CEC, no metabolism study was reported for these cathinones. With the ultimate goal of overcoming this gap, these cathinones were incubated in vitro in human and rat liver microsomes in the presence of Phase I and II (glucuronidation) co-factors, using α-pyrrolidinovalerophenone (α-PVP) as positive control. The metabolite identification was performed by liquid chromatography coupled to tandem high resolution mass spectrometry (LC-HRMS/MS). This allowed the identification of multiple Phase I and glucuronide metabolites of the selected cathinones. Additionally, a new glucuronide conjugate, derived from the recreational drug α-PVP, was herein identified for the first time. Importantly, we have demonstrated that 4-MDMC and 4-MDEC can act as prodrugs of the controlled substances 4-MMC and 4-MEC, respectively. The metabolites herein identified are expected to play an important role not only by acting as potential selective biomarkers of the intake of the synthetic cathinones selected for this study but also to understand their potential adverse effects and link these causative agents to toxicities, thereby helping in the treatment of non-fatal intoxications.eng
dc.description.sponsorshipWe thank FCT (Fundação para a Ciência e Tecnologia) for funding the strategic projects UIDB/00100/2020 and UIDP/00100/2020 to CQE - Centro de Química Estrutural, UIDB/04046/2020 and UIDP/04046/2020 to BioISI - Biosystems & Integrative Sciences Institute, UIDB/04292/2020 and UIDP/04292/2020 to MARE - Marine and Environmental Sciences Centre, and the research projects PTDC/QUIQAN/32242/2017, PTDC/QUI-QIN/28662/2017, PTDC/QUI-QOR/29664/2017, and POINT4PAC project (SAICTPAC/0019/2015-LISBOA-01-0145-FEDER-016405).
dc.identifier.citationLopes BT, Caldeira MJ, Gaspar H and Antunes AMM (2021) Metabolic Profile of Four Selected Cathinones in Microsome Incubations: Identification of Phase I and II Metabolites by Liquid Chromatography High Resolution Mass Spectrometry. Front. Chem. 8:609251. doi: https://doi.org/10.3389/fchem.2020.609251.
dc.identifier.doi10.3389/fchem.2020.609251
dc.identifier.eissn2296-2646
dc.identifier.urihttp://hdl.handle.net/10400.8/16084
dc.language.isoeng
dc.peerreviewedyes
dc.publisherFrontiers Media
dc.relationCentro de Química Estrutural
dc.relationCentro de Química Estrutural
dc.relationBiosystems and Integrative Sciences Institute
dc.relationBiosystems and Integrative Sciences Institute
dc.relationMarine and Environmental Sciences Centre
dc.relationMarine and Environmental Sciences Centre
dc.relationFighting metastatic cancers: prime time for ruthenium
dc.relationDRUG DISCOVERY FOR p53 PPI-TARGETS
dc.relation.hasversionhttps://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.609251/full
dc.relation.ispartofFrontiers in Chemistry
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject4-CEC
dc.subject4Cl-PVP
dc.subject4-MDEC
dc.subject4-MDMC
dc.subjectLC-HRMS
dc.subjectglucuronides
dc.subjectPhase I
dc.subjectmetabolites
dc.titleMetabolic Profile of Four Selected Cathinones in Microsome Incubations: Identification of Phase I and II Metabolites by Liquid Chromatography High Resolution Mass Spectrometryeng
dc.typejournal article
dcterms.referenceshttps://www.frontiersin.org/articles/10.3389/fchem.2020.609251/full#supplementary-material
dspace.entity.typePublication
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oaire.awardTitleCentro de Química Estrutural
oaire.awardTitleCentro de Química Estrutural
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleMarine and Environmental Sciences Centre
oaire.awardTitleMarine and Environmental Sciences Centre
oaire.awardTitleFighting metastatic cancers: prime time for ruthenium
oaire.awardTitleDRUG DISCOVERY FOR p53 PPI-TARGETS
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oaire.awardURIhttp://hdl.handle.net/10400.8/16082
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oaire.citation.endPage13
oaire.citation.startPage1
oaire.citation.titleFrontiers in Chemistry
oaire.citation.volume8
oaire.fundingStream6817 - DCRRNI ID
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oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamConcurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017
oaire.fundingStreamConcurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameGuerreiro Galla Gaspar
person.givenNameHelena Margarida
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Consumption of synthetic cathinones, the second largest class of new psychoactive substances (NPS) reported worldwide, represents a serious public health risk. One of the biggest challenges created by the rapid spread of NPS on the illegal drug market is the discovery of selective biomarkers for their detection in biological matrices, which is only possible through the study of their metabolic profile. The synthetic cathinones 4′-methyl-N,N-dimethylcathinone (4-MDMC), 4′-methyl-N,N-diethylcathinone (4-MDEC), 4′-chloro-α-pyrrolidinovalerophenone (4Cl-PVP), and 4′-chloroethylcathinone (4-CEC) are NPS recently seized in Europe, and, with the exception of 4-CEC, no metabolism study was reported for these cathinones. With the ultimate goal of overcoming this gap, these cathinones were incubated in vitro in human and rat liver microsomes in the presence of Phase I and II (glucuronidation) co-factors, using α-pyrrolidinovalerophenone (α-PVP) as positive control. The metabolite identification was performed by liquid chromatography coupled to tandem high resolution mass spectrometry (LC-HRMS/MS). This allowed the identification of multiple Phase I and glucuronide metabolites of the selected cathinones. Additionally, a new glucuronide conjugate, derived from the recreational drug α-PVP, was herein identified for the first time. Importantly, we have demonstrated that 4-MDMC and 4-MDEC can act as prodrugs of the controlled substances 4-MMC and 4-MEC, respectively. The metabolites herein identified are expected to play an important role not only by acting as potential selective biomarkers of the intake of the synthetic cathinones selected for this study but also to understand their potential adverse effects and link these causative agents to toxicities, thereby helping in the treatment of non-fatal intoxications.
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