3-Fluorophenmetrazine, a fluorinated analogue of phenmetrazine: Studies on in vivo metabolism in rat and human, in vitro metabolism in human CYP isoenzymes and microbial biotransformation in Pseudomonas Putida and wastewater using GC and LC coupled to (HR)-MS techniques

Mardal, Marie; Miserez, Bram; Bade, Richard; Portolés, Tania; Bischoff, Markus; Hernández, Félix; Meyer, Markus R.

doi:10.1016/j.jpba.2016.06.011

Cited by 16 publications

(16 citation statements)

References 22 publications

(31 reference statements)

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“…Urine specimens (with and without enzymatic cleavage) were screened for metabolites in MRM mode using the metabolites and mass transitions given by Mardal et al The LC‐gradient (total flow rate 0.3 mL/min, column oven temperature 40 °C, autosampler temperature 10 °C, injection volume 10 μL) for the analysis of the urine specimens differed from the gradient described in 2.3 to achieve better separation of the more polar metabolites and was as follows: starting with 1% mobile phase B for 5 minutes the gradient was increased to 6% mobile phase B within 5 minutes. Linearly increased, the gradient reached 20% B at 12 minutes and was further increased to 50% B within 1 minute.…”

Section: Methodsmentioning

confidence: 99%

“…They also found evidence for catecholamine‐selective releasing properties comparable to the parent compound phenmetrazine. The first in vivo and in vitro as well as microbial metabolic studies on 3‐FPM were published by Mardal et al However, reports on concentrations in biological material and toxicological effects are scarce. Bäckberg et al reported on serum samples collected from 15 intoxicated individuals with 3‐FPM concentrations ranging between 2.7 and 1,416 ng/mL and 14 urine samples with concentrations ranging from 8.2 to 30,857 ng/mL (1.0 to 6,857 μg/mmol creatinine) .…”

Section: Introductionmentioning

confidence: 99%

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Method validation and preliminary pharmacokinetic studies on the new designer stimulant 3‐fluorophenmetrazine (3‐FPM)

Grumann

Huppertz

Bisel

et al. 2019

Drug Testing and Analysis

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Pharmaceutical research not only provides the basis for the development of new medicinal products but also for the synthesis of new drugs of abuse. 3‐Fluorophenmetrazine (3‐FPM), a fluorinated derivative of the anorectic phenmetrazine, was first patented in 2011 and appeared on the drug market in 2014. Though invented for potential medical purposes, pharmacokinetic data on this compound, crucial for interpreting forensic as well as clinical cases, are not available. Therefore, a liquid chromatography−electrospray ionization−tandem mass spectrometry (LC−ESI−MS/MS) method for the detection of 3‐FPM in serum, urine, and oral fluid was developed, validated for urine and serum, and used to quantify 3‐FPM in samples obtained during a controlled self‐experiment. The method proved to be linear, selective and sufficiently sensitive. The limits of detection (LODs) were 0.1 ng/mL, 0.2 ng/mL, and 0.05 ng/mL in serum, urine, and oral fluid. Inter‐day precision and intra‐day precision (RSD) in serum samples were below 6.3% and below 8.5%, respectively. The highest serum concentration (cmax) of 210 ng/mL was reached 2.5 hours (tmax) after ingestion. The elimination half‐life and the volume of distribution were calculated to be approx. 8.8 hours and 400 L (5.3 L/kg). 3‐FPM could be detected in serum and urine up to 82 hours and 116 hours, respectively. It was still detected in the last oral fluid sample taken 55 hours after ingestion. 3‐FPM was mainly excreted unchanged. Main metabolic reactions were aryl‐hydroxylation and N‐hydroxylation. Interestingly, the product of oxidative ring opening (2‐amino‐1‐(3‐fluorophenyl)propan‐1‐ol) showed the largest window of detection in the self‐experiment.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Method validation and preliminary pharmacokinetic studies on the new designer stimulant 3‐fluorophenmetrazine (3‐FPM)

Grumann

Huppertz

Bisel

et al. 2019

Drug Testing and Analysis

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“…11 Pharmacological studies on the three fluorophenmetrazine isomers revealed that 3-FPM and its positional isomers are substratetype releasing agents at monoamine transporters with marked potency at DAT and NET, which suggests that these compounds might display abuse and dependence liability. 10 A recent study by Bäckberg et al 14 3-FPM has also been detected in biological samples obtained from a multiple-drug fatality.…”

Section: Introductionmentioning

confidence: 93%

“…1 Emerging evidence suggests that phendimetrazine may be an efficacious candidate treatment for cocaine dependence. 10,11 The manipulation of the phenmetrazine structure by substitution on the phenyl or morpholine rings creates a variety of suitable candidates for the NPS market. 10,11 The manipulation of the phenmetrazine structure by substitution on the phenyl or morpholine rings creates a variety of suitable candidates for the NPS market.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

McLaughlin

Baumann

Kavanagh

et al. 2018

Drug Testing and Analysis

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The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3-methyl-2-phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3-fluorophenmetrazine (3-FPM), namely 4-methylphenmetrazine (4-MPM), and 3-methylphenmetrazine (3-MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant-like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4-MPM in two of the samples and 3-MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2-MPM and 3-MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4-MPM may display entactogen properties more similar to 3,4-methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.

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“…GC-TOF MS or GC-QqTOF MS was primarily applied for studying human exposures to persistent organic chemicals (Hernández et al, 2009b, Kazda et al, 2004, Focant et al, 2004, Megson et al, 2015, Fan et al, 2014). Trends in the GC-HRMS applications were reviewed recently ((Hernández et al, 2011a, Hernández et al, 2012)), and applied to metabolites in human and rat urine (Mardal et al, 2016) and environmental chemicals in food (Portolés et al, 2014b, Nácher-Mestre et al, 2014), water (Nácher-Mestre et al, 2011, Portolés et al, 2014a) and packaging material (Onghena et al, 2015, Cherta et al, 2015). These GC-HRMS approaches can be applied for studying the volatiles and non-polar chemicals space of the human exposome with sensitivity and limits of detection in the range between higher pico-molar to lower micro-molar concentrations (Smolinska et al, 2014, Macherone, 2013).…”

Section: Applications Of Time-of-flight Mass Spectrometry For Studmentioning

confidence: 99%

Trends in the application of high-resolution mass spectrometry for human biomonitoring: An analytical primer to studying the environmental chemical space of the human exposome

Andra

Austin

Patel

et al. 2017

Environment International

125

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Global profiling of xenobiotics in human matrices in an untargeted mode is gaining attention for studying the environmental chemical space of the human exposome. Defined as the study of a comprehensive inclusion of environmental influences and associated biological responses, human exposome science is currently evolving out of the metabolomics science. In analogy to the latter, the development and applications of high resolution mass spectrometry (HRMS) has shown potential and promise to greatly expand our ability to capture the broad spectrum of environmental chemicals in exposome studies. HRMS can perform both untargeted and targeted analysis because of its capability of full- and/or tandem-mass spectrum acquisition at high mass accuracy with good sensitivity. The collected data from target, suspect and non-target screening can be used not only for the identification of environmental chemical contaminants in human matrices prospectively but also retrospectively. This review covers recent trends and advances in this field. We focus on advances and applications of HRMS in human biomonitoring studies, and data acquisition and mining. The acquired insights provide stepping stones to improve understanding of the human exposome by applying HRMS, and the challenges and prospects for future research.

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3-Fluorophenmetrazine, a fluorinated analogue of phenmetrazine: Studies on in vivo metabolism in rat and human, in vitro metabolism in human CYP isoenzymes and microbial biotransformation in Pseudomonas Putida and wastewater using GC and LC coupled to (HR)-MS techniques

Cited by 16 publications

References 22 publications

Method validation and preliminary pharmacokinetic studies on the new designer stimulant 3‐fluorophenmetrazine (3‐FPM)

Method validation and preliminary pharmacokinetic studies on the new designer stimulant 3‐fluorophenmetrazine (3‐FPM)

Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

Trends in the application of high-resolution mass spectrometry for human biomonitoring: An analytical primer to studying the environmental chemical space of the human exposome

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