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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.

ABSTRACT: 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-?-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 ?-pyrrolidinovalerophenone (?-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 ?-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.

SUBMITTER: Lopes BT

PROVIDER: S-EPMC7835677 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

Lopes Beatriz T BT Caldeira Maria João MJ Gaspar Helena H Antunes Alexandra M M AMM

Frontiers in chemistry 20210112

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'-met ...[more]

PMID: 33511100

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Project description:BackgroundPrediction of delivery is important for assessing due dates, providing adequate prenatal care, and suggesting appropriate interventions in preterm and post-term pregnancies. Recent metabolomic findings suggested that the temporal abundance information of metabolome can be used to predict delivery timing with high accuracy in a cohort of healthy women. However, a targeted and quantitative assay is required to further validate the clinical performance and utility of this group of metabolomic candidates in delivery prediction with a larger and independent cohort.MethodLC-MS/MS quantitative assays were applied to determine the plasma concentrations of four steroid metabolites, including oestriol-16-glucuronide (E3-16-Gluc), 17-alpha-hydroxyprogesterone (17-OHP), tetrahydrodeoxycorticosterone (THDOC), and androstane-3,17-diol (A-3,17-Diol) in asymptomatic women of singleton pregnancies (≥30th gestational weeks). Subsequent statistical analysis was conducted to assess the performance of the above candidates in delivery prediction.ResultUsing LC-MS/MS, four steroids were separated and quantified in 5.5 min. The coefficients of variation (CVs) of the four analytes at the lower limit of quantification ranged from 7.9% to 14.6%, with the R2 values greater than 0.990 in the calibration curves. Of the 585 recruited pregnant women who ended up with spontaneous delivery, 17.1% and 82.9% of the subjects delivered within and after 7 days since plasma collection, respectively. In the receiver operator curve analysis, the gestational age-adjusted area under the curve of the combined measurements of E3-16-Gluc and 17-OHP was 0.69 (95% CI: 0.60-0.76), with the sensitivity of 87.0% (95% CI: 78.8%-92.9%) and specificity of 60.2% (95% CI: 55.7%-64.6%). Moreover, the positive and the negative predictive values were 28.3%-34.0% and 93.1%-97.4% respectively for this combined panel.ConclusionWe performed analytical and clinical validation of a quantitation LC-MS/MS panel for the four steroids in the plasma of pregnant women. The steroid metabolites panel of E3-16-Gluc and 17-OHP was potentially useful for predicting delivery within one week in asymptomatic women of singleton pregnancies. Key messagesA quantitative LC-MS/MS assay for determining the plasma levels of 17-OHP, THDOC, A-3,17-Diol and E3-16-Gluc was developed and validated, in order to evaluate their predictive performance in asymptomatic delivery of singleton pregnancy. The levels of E3-16-Gluc and 17-OHP were found to be significantly elevated at the time of sampling in women that delivered within one week and their combinational testing may be potentially useful in delivery prediction.

Dataset Information

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

Publications

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

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