Metabolic profiling of four synthetic stimulants, including the novel indanyl-cathinone 5-PPDi, after human hepatocyte incubation

Fabregat‐Safont, David; Mardal, Marie; Sancho, Juan V.; Hernández, Félix; Línnet, Kristían; Ibáñez, María

doi:10.1016/j.jpha.2019.12.006

Cited by 10 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A first attempt to investigate the metabolic profile of 4-CEC was performed in human hepatocytes (Fabregat-Safont et al, 2020 ). However, no metabolites were identified for this cathinone in this in vitro system.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, 4-MDEC was the most cytotoxic cathinone tested in HepG2 cells, in our previous work (Gaspar et al, 2018 ) and 4-MDMC was one of the five most seized cathinones in EU, during 2016, while 4-CEC was the second one with highest overall quantities of seized products (EMCDDA, 2017 ). All the four selected cathinones are controlled in Portugal (Decree Law 15/93 and Decree Law 54/2013) and only 4-CEC has already been subject of metabolism studies (Fabregat-Safont et al, 2020 ; Wagmann et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The same strategy—pHH incubation and subsequent analysis by LC–HRMS (Q‐Orbitrap instrument in this case) using DDA mode—was used for the first reported metabolic pathway of the synthetic cathinone 5‐PPDi 54 . In addition to the metabolites searching based on expected biotransformations, the compounds detected in the MS scan of 5‐PPDi pHH incubations were automatically compared with blank pHH incubations, using an appropriate processing software 54 . This approach, also known as binary comparison, is typically used in metabolism experiments when a control sample is available 38 .…”

Section: Understanding Nps Metabolism Based On Ms Datamentioning

confidence: 99%

“…The main objective is to detect unexpected metabolites, not considered in the expected biotransformation list, and to discard possible false positives from the incubation media that could present the same exact mass than a putative metabolite. In this way, only those compounds present in 5‐PPDi pHH incubations but not in blank pHH incubations are considered as potential metabolites, performing subsequent automated MS/MS fragmentation to complement the information obtained 54 . When the detected compound presented MS/MS fragmentation compatible with a metabolic biotransformation, the MS/MS spectra were again acquired at three different collision energies, in order to obtain the maximum information possible 54 .…”

Section: Understanding Nps Metabolism Based On Ms Datamentioning

confidence: 99%

“…In this way, only those compounds present in 5‐PPDi pHH incubations but not in blank pHH incubations are considered as potential metabolites, performing subsequent automated MS/MS fragmentation to complement the information obtained 54 . When the detected compound presented MS/MS fragmentation compatible with a metabolic biotransformation, the MS/MS spectra were again acquired at three different collision energies, in order to obtain the maximum information possible 54 . The observed metabolite fragmentation was finally compared with 5‐PPDi MS/MS fragmentation, in order to locate the position of the biotransformation 54 .…”

Section: Understanding Nps Metabolism Based On Ms Datamentioning

confidence: 99%

See 1 more Smart Citation

The key role of mass spectrometry in comprehensive research on new psychoactive substances

Fabregat‐Safont¹,

Sancho²,

Hernández³

et al. 2020

J Mass Spectrom

Self Cite

View full text Add to dashboard Cite

New psychoactive substances (NPS) are a wide group of compounds that try to mimic the effects produced by the ‘classical’ illicit drugs, including cannabis (synthetic cannabinoids), cocaine and amphetamines (synthetic cathinones) or heroin (synthetic opioids), and which health effects are still unknown for most of them. Nowadays, more than 700 compounds are being monitored by official organisms, some of which have been recently identified in seizures and/or intoxication cases. Toxicological analysis plays a pivotal role in NPS research. A comprehensive investigation on NPS, from the first identification of a novel substance until its detection in drug users to help in diagnostics and medical treatment, requires the use of a wide variety of instruments and analytical strategies. This paper illustrates the key role of mass spectrometry (MS) along a comprehensive investigation on NPS. The synthetic cannabinoid XLR‐11 and the synthetic cathinone 5‐PPDi have been chosen as representative substances of the most consumed NPS families. Moreover, both compounds have been investigated at our laboratory in different stages of the three‐step strategy considered in this article. The initial identification and characterisation of the compound in consumption products, the first reported metabolic pathway and the development of analytical methodologies for its determination (and/or their metabolites) in different toxicological samples are described. The analytical strategies and MS instruments are briefly discussed to show the reader the possibilities that MS instrumentation offer to analytical scientists. This publication aims to be a starting point for those interested on the NPS research field from an analytical chemistry point of view.

show abstract

The key role of mass spectrometry in comprehensive research on new psychoactive substances

Fabregat‐Safont¹,

Sancho²,

Hernández³

et al. 2021

J Mass Spectrom

Self Cite

View full text Add to dashboard Cite

This month's Special Feature is authored by four accomplished investigators from the Department of Physical and Analytical Chemistry, University Jaume I, Castellón de la Plana, Spain. In their article, Dr. Ibáñez and colleagues direct their attention towards issues relating to new psychoactive substances (NPS), or emerging designer drugs, a heterogeneous group of compounds that aim to mimic the actions of ‘classical’ illicit drugs and circumvent scheduling guidelines. Each year these drugs contribute to a growing number of drug‐related adverse events and deaths. The authors describe their work by way of a three‐step strategy for the analysis of these agents by mass spectrometry: first, detection and analytical characterization of the NPS; second, metabolic and pharmacokinetics studies to select the most suitable biomarkers of their consumption; and third, the detection, identification and quantification of these biomarkers in biological tissues and fluids. They discuss the application of a range of mass spectrometric techniques, including conventional approaches such as combined liquid chromatography‐mass spectrometry, but also the more recent adoption of direct ionization sources for the rapid identification of seized lots of drugs. To illustrate their points this Special Feature focuses on two model psychoactive substances: the synthetic cannabinoid XLR‐11 and the synthetic cathinone 5‐PPDi. Their Special Feature illustrates some of the challenges involved in the analysis of new psychoactive substances and highlights the essential role of mass spectrometry in this important and rapidly evolving area.

show abstract

Metabolic profiling of four synthetic stimulants, including the novel indanyl-cathinone 5-PPDi, after human hepatocyte incubation

Cited by 10 publications

References 32 publications

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

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

The key role of mass spectrometry in comprehensive research on new psychoactive substances

The key role of mass spectrometry in comprehensive research on new psychoactive substances

Contact Info

Product

Resources

About