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<p>Ring-substituted synthetic cathinones represent a major subgroup within new psychoactive substances. This study investigated the in vitro toxicokinetics of the three 4-methoxy-substituted representatives 4MeO-NE-BP (4’-methoxy-<i>N</i>-ethylbutyrophenone), 4MeO-αP-BP (4’-methoxy-α-pyrrolidinobutyrophenone), and 4MeO-αP-VP (4’-methoxy-α-pyrrolidinovalerophenone) and the three related novel 4-methylthio analogs 4MeS-NE-BP (4’-methylthio-<i>N</i>-ethylbutyrophenone), 4MeS-αP-BP&#xa0;(4’-methylthio-α-pyrrolidinobutyrophenone), and 4MeS-αMor-PrP (4’-methylthio-2-morpholinopropiophenone). This included plasma protein binding (PPB), phase&#xa0;I and phase II metabolism in pooled human liver S9 fraction (pHLS9) and HepaRG cells, and monooxygenases activity. Methoxycathinones exhibited lower PPB (~ 40–60%) compared to methylthiocathinones (~ 85%). Predominant phase I metabolic reactions included <i>O</i>-/<i>S</i>-demethylation and hydroxylation, with additional transformations such as <i>N</i>-dealkylation, <i>N</i>-oxidation, and oxo reduction. Phase II conjugation reactions, such as glucuronidation and sulfation, were observed post-demethylation. Overall, 42 and 45 metabolites were identified in pHLS9 and HepaRG systems, respectively, with metabolite number increasing alongside alkyl chain length and heterocyclic substitution. All compounds were substrates for multiple monooxygenases, suggesting a low risk for drug–drug interactions. Based on metabolic stability and abundance, parent compounds and <i>O</i>-/<i>S</i>-desmethyl and hydroxylated metabolites might be proposed as urinary screening targets in clinical and forensic toxicology, as well as doping control settings.</p>

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In vitro toxicokinetics and metabolic profiling of methoxycathinones and methylthiocathinones using human liver systems and hyphenated mass spectrometry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Matthias D. Kroesen,
  • Tanja M. Gampfer,
  • Lea Wagmann,
  • Pierce V. Kavanagh,
  • Simon D. Brandt,
  • Markus R. Meyer

摘要

Ring-substituted synthetic cathinones represent a major subgroup within new psychoactive substances. This study investigated the in vitro toxicokinetics of the three 4-methoxy-substituted representatives 4MeO-NE-BP (4’-methoxy-N-ethylbutyrophenone), 4MeO-αP-BP (4’-methoxy-α-pyrrolidinobutyrophenone), and 4MeO-αP-VP (4’-methoxy-α-pyrrolidinovalerophenone) and the three related novel 4-methylthio analogs 4MeS-NE-BP (4’-methylthio-N-ethylbutyrophenone), 4MeS-αP-BP (4’-methylthio-α-pyrrolidinobutyrophenone), and 4MeS-αMor-PrP (4’-methylthio-2-morpholinopropiophenone). This included plasma protein binding (PPB), phase I and phase II metabolism in pooled human liver S9 fraction (pHLS9) and HepaRG cells, and monooxygenases activity. Methoxycathinones exhibited lower PPB (~ 40–60%) compared to methylthiocathinones (~ 85%). Predominant phase I metabolic reactions included O-/S-demethylation and hydroxylation, with additional transformations such as N-dealkylation, N-oxidation, and oxo reduction. Phase II conjugation reactions, such as glucuronidation and sulfation, were observed post-demethylation. Overall, 42 and 45 metabolites were identified in pHLS9 and HepaRG systems, respectively, with metabolite number increasing alongside alkyl chain length and heterocyclic substitution. All compounds were substrates for multiple monooxygenases, suggesting a low risk for drug–drug interactions. Based on metabolic stability and abundance, parent compounds and O-/S-desmethyl and hydroxylated metabolites might be proposed as urinary screening targets in clinical and forensic toxicology, as well as doping control settings.