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.
The emergence of potentially dangerous new psychoactive substances (NPS) is challenging for forensic laboratories, as well as the ability to develop and validate methods for a rapid and unambiguous monitoring of these compounds. Thereupon, the aim of this work was to establish a methodology for the identification and quantification of four synthetic cathinones already seized in Portugal [4-chloroethcathinone (4-CEC), α-pyrrolidinovalerophenone (α-PVP), 4-chloro-pyrrolidinovalerophenone (4-Cl-PVP) and methylenedioxypyrovalerone (MDPV)] in whole blood samples, using gas chromatography coupled to mass spectrometry (GC–MS). The analytes were extracted from blood by solid-phase extraction (SPE) and derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) with 5% trimethylchlorosilane (TMCS). For all analytes, linearity was observed from 25 (lower limit of quantification, LLOQ) to 800 ng/mL, with coefficients of determination higher than 0.99. The limits of detection (LOD) were 5 ng/mL for α-PVP, 4-Cl-PVP and MDPV and 25 ng/mL for 4-CEC. The method was selective, precise and accurate and the extraction efficiency was higher than 85% for all analytes. The target cathinones were stable under different stock conditions, being MDPV the most stable and 4-CEC the least stable compound. The validated analytical method was then applied to real samples that previously tested positive for amphetamines, but no positive samples were found for the cathinones under study. The present method describes for the first time the quantification of 4-CEC and 4-Cl-PVP in whole blood samples by GC–MS, allowing their accurate determination in forensic situations where the compounds are involved.
In this work we present a detailed study of the mechanism of photochemistry and thermal reactions, as well as of the kinetics of flavothione (FLT) in ethanol. Furthermore, we analyzed how the hydroxysubstitution pattern of FLT influenced both the kinetics and the mechanism relative to the parent FLT. We show that the primary photochemical reaction of FLT in the absence of oxygen is hydrogen (H)-atom abstraction from the solvent by way of the excited triplet state of FLT. Several products result from thermal reactions of the resulting semireduced FLTH* radical, including more than one dimer. A full mechanism is proposed, and the relevant rate constants are evaluated. On the other hand, in the presence of oxygen and a low concentration of FLT, we found that the principal photoproduct is the parent flavone (FL). The reaction leading to photoxidation is not via 1O2 attacking a thione, but instead, it is via a reaction of the FLTH* radical with ground state oxygen. The kinetic data also demonstrate that the relative values of concentrations of reactants and the rate constants of the reactions can control the dominance of one mechanism over others. We also have examined the photochemical mechanisms and kinetics for several hydroxyflavothiones (n-OHFLT) and compared them with FLT itself. We have found that the photochemical mechanism radically changes depending on the positions of substitution. These differences are directly related to the ordering of the excited states of the n-OHFLT. Specifically, FLT with lowest 3n,pi* states (FLT, 6-hydroxyflavothione, 7-hydroxyflavothione and 7,8-dihydroxyflavothione) efficiently abstract H atoms to give the semireduced radical of the thione. The radical can (1) dimerize to form two different dimers; (2) react with oxygen to produce the parent FL; and (3) recombine with the solvent radical to yield the original FLT. In contrast, FLT with lowest 3pi,pi* states (3-hydroxyflavothione, 3,6-dihydroxyflavothione and 3,7-dihydroxyflavothione) behave as photosensitizers of oxygen to form singlet oxygen, which then reacts with the ground state of the substituted FLT. Finally, when T2(pi,pi*) is above S1(n,ppi*), as for 5-hydroxyflavothione and 5,7-dihydroxyflavothione, both the S1(n,pi*) --> T1(n,pi*) intersystem crossing and photodegradation are inefficient.
The innovation of the new psychoactive substances (NPS) market requires the rapid identification of new substances that can be a risk to public health, in order to reduce the damage from their use. Twelve seized products suspected to contain illicit substances were analyzed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), gas chromatography coupled to mass spectrometry (GC-MS), and nuclear magnetic resonance spectroscopy (NMR). Synthetic cathinones (SCat) were found in all products, either as a single component or in mixtures. Infrared spectra of all products were consistent with the molecular structure of SCat, showing an intense absorption band at 1700–1674 cm−1, corresponding to the carbonyl stretching, a medium/strong peak at 1605–1580 cm−1, indicating stretching vibrations in the aromatic ring (C=C) and bands with relative low intensity at frequencies near 2700–2400 cm−1, corresponding to an amine salt. It was possible to identify a total of eight cathinone derivatives by GC-MS and NMR analysis: 4’-methyl-α-pyrrolidinohexanophenone (MPHP), α-pyrrolidinohexanophenone (α-PHP), 3-fluoromethcathinone (3-FMC), methedrone, methylone, buphedrone, N-ethylcathinone, and pentedrone. Among the adulterants found in these samples, caffeine was the most frequently detected substance, followed by ethylphenidate. These results highlight the prevalence of SCat in seized materials of the Portuguese market. Reference standards are usually required for confirmation, but when reference materials are not available, the combination of complementary techniques is fundamental for a rapid and an unequivocal identification of such substances.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.