Abstract
PurposeIn this study, the phase I and II metabolic pathways of 4,4′-dimethylaminorex were characterized to select the marker(s) of intake allowing the unequivocal identification of this novel psychoactive substance in urine samples.MethodsThe metabolic profile of 4,4′-dimethylaminorex was characterized using both in vitro and in vivo models. In detail, for the in vitro experiments, either pooled human liver microsomes or recombinant cytochrome P450 isoforms were selected, whereas the in vivo investigation was performed on male mice ICR (CD-1®). Sample preparation included enzymatic hydrolysis followed by liquid/liquid extraction. The instrumental analysis was performed by ultra-high-performance liquid chromatography coupled to either high- or low-resolution tandem mass spectrometry.ResultsFive metabolic products were isolated only for the cis-isomer: the phase I metabolic reactions included hydrolysis, carboxylation, hydroxylation, and carbonylation. CYP2D6 was the principal isoenzyme involved, and the incubation in the presence of different allelic variants showed significant alteration on the metabolic profile. Once formed, the phase I metabolites underwent extensive conjugation. Not only the most abundant compounds detected, but also those with the most extended window of detection, were the carboxylated and the hydroxylated metabolites. These analytes together with the parent compound were selected as the most suitable markers of intake.ConclusionsKnowledge of the metabolic profiles of the new drugs is essential for their fast identification. Phase I and phase II metabolites of 4,4′-dimethylaminorex were identified and selected as markers of intake, to be considered as the most suitable analytical targets in forensic toxicology.
Highlights
Since the 1960s, new psychoactive substances (NPS), known as “designer” drugs, became a global problem, which has been continuously expanding [1]
4,4′-Dimethylaminorex (4-methyl-5-(4-methylphenyl)4,5-dihydro-1,3-oxazol-2-amine, known as 4,4′DMAR, or DMAR) is a synthetic psychostimulant and anorexigenic substance structurally correlated to the controlled drugs aminorex ((RS)-5-phenyl-4,5-dihydro1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, known as 4-MAR) [7, 8]
The use of human liver microsomes (HLM) and recombinant cytochrome P450 isoforms allowed to reproduce metabolism in humans and characterize the enzymatic isoforms involved in the metabolic pathways detected, whereas the analysis of urine samples collected from mice allowed to define the window of detection of the parent compounds and its main metabolites, and to select the most appropriate target compound(s) to detect drugs after recent intake
Summary
Since the 1960s, new psychoactive substances (NPS), known as “designer” drugs, became a global problem, which has been continuously expanding [1]. Besides the traditional amphetamine-type designer drugs, which have been widely abused for decades, the number of newly detected psychoactive substances has been increasing dramatically At present, they include several different classes of drugs of abuse, e.g., cannabimimetics, fentanyls, piperidines, tryptamine derivatives and the groups of phenethylamines [1, 2]. 4,4′-Dimethylaminorex (4-methyl-5-(4-methylphenyl)4,5-dihydro-1,3-oxazol-2-amine, known as 4,4′DMAR, or DMAR) is a synthetic psychostimulant and anorexigenic substance structurally correlated to the controlled drugs aminorex ((RS)-5-phenyl-4,5-dihydro1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, known as 4-MAR) [7, 8]. Both aminorex and 4-MAR were introduced into the market in 1960s as appetite suppressants, but were subsequently withdrawn due to fatal complications related to pulmonary hypertension [9, 10]. Due to two chiral centres within the oxazoline ring, 4,4′-DMAR exists in four enantiomers or two different ((±)-cis and (±)-trans) racemates
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