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Isabelle Fourel - One of the best experts on this subject based on the ideXlab platform.
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Mass spectrometry characterization of anticoagulant rodenticides and hydroxyl metabolites.
Rapid communications in mass spectrometry : RCM, 2020Co-Authors: Isabelle Fourel, Alexandra Berlioz-barbier, Etienne BenoitAbstract:RATIONALE Anticoagulant rodenticides (ARs) are used worldwide for rodent population control to protect human health and biodiversity, and to prevent agricultural and economic losses. Rodents may develop a metabolic resistance to ARs. In order to help understand such metabolic resistance, mass spectrometry was used to position the hydroxylated group of hydroxyl metabolites of second-generation ARs (SGARs). METHODS Most AR pesticides are derived from the 4-hydroxycoumarin/thiocoumarin family. We used low-resolution and high-resolution mass spectrometry to understand the fragmentation pathways of the ARs and their respective metabolites, and to better define the structure of their tandem mass spectrometry product ions. RESULTS Seven specific product ions were evidenced for five ARs, with their respective chemical structures. Those ions were obtained as well from the mass spectra of the hydroxyl metabolites of four SGARs, difenacoum (DFM), brodifacoum (BFM), difethialone (DFTL) and Flocoumafen (FLO), with different positions of the hydroxyl group. CONCLUSIONS The differences in chemical structure between DFM on the one hand and BFM, FLO and DFTL on the other could explain the differences in bioavailability between these two groups of molecules. The defined product ions will be used to investigate the part played by the metabolic issue in the field resistance of SGARs.
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Management of Rodent Populations by Anticoagulant Rodenticides: Toward Third-Generation Anticoagulant Rodenticides
Drug Metabolism and Disposition, 2017Co-Authors: Marlène Damin-pernik, Isabelle Fourel, Etienne Benoit, Bernadette Espana, Sébastien Lefebvre, Hervé Caruel, Virginie LattardAbstract:Second-generation anticoagulant rodenticides (SGARs) have been used since the 1980s for pest management. They are highly efficient even in warfarin-resistant rodents. Nevertheless, because of their tissue persistence, nontarget poisoning by SGARs is commonly described in wildlife. Due to this major problem, a new generation of anticoagulants must be developed to limit this risk. This study proposes a method of developing a new generation of anticoagulant rodenticides by revisiting the old SGARs based on the concept of stereochemistry. Each current SGAR is a mixture of diastereomers. Diastereomers of each compound were purified, and their biologic properties were compared by determining their ability to inhibit vitamin K epoxide reductase (VKOR) activity involved in the activation of vitamin K-dependent clotting factors and their toxicokinetic properties. Systematically, for each SGAR, both diastereomers are as effective in inhibiting VKOR activity. However, their toxicokinetic properties are very different, with one of the two diastereomers always more rapidly cleared than the other one. For all SGARs except Flocoumafen, the less persistent diastereomer is always the less predominant isomer present in the current mixture. Therefore, the development of baits containing only the less persistent diastereomer would avoid the ecotoxicological risk associated with their use without decreasing their efficacy.
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Core-shell LC-MS/MS method for quantification of second generation anticoagulant rodenticides diastereoisomers in rat liver in relationship with exposure of wild rats.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2016Co-Authors: Isabelle Fourel, Marlène Damin-pernik, Etienne Benoit, Virginie LattardAbstract:Second generation anticoagulant rodenticides (SGARs), pesticides used worldwide to control rodent populations, exist in two diastereoisomer chemical species because they own two stereogenic centers. A core-shell LC-MS/MS multi-residue method for comprehensive quantitative analysis of the diastereoisomers of five SGARs as well as three first generation anticoagulant rodenticide molecules has been fully validated in liver of rats according to a bioanalytical guideline. A core-shell column (superficially porous particles) has been chosen for its ability to separate the diastereomers of bromadiolone, difenacoum, brodifacoum, Flocoumafen and difethialone and for its robustness to rat liver extracts. The highly selective chromatographic separation of the diastereoisomers contributes to good signal to noise ratios and then enhances the sensitivity of the method compared to the ones of fully porous columns. An elution gradient has been optimized with 10mM ammonium acetate and acetonitrile as aqueous/organic mobile phase respectively. Triple quadrupole mass detector has been used to achieve specifity and LLOQ from 0.92 to 2.2ng/g for each diastereoisomer, or first generation anticoagulant rodenticides. Then we evidenced diastereoisomeric ratios in liver of rats issued from not controlled exposure of wild rats (Rattus norvegicus) trapped in a French Parisian park through a campaign of rodent eradication. We compared them to diastereoisomeric ratios in SGARs commercial baits that contain both isomers, and showed that one of the two diastereoiomers had nearly disappeared in liver of rats. The proportions of cis-bromadiolone and trans-difenacoum were really lowered compared to the baits: 5/7 and 9/12 rats had only trans-bromadiolone and cis-difenacoum hepatic residues respectively. Liver persistence of the two diastereoisomers of bromadiolone and difenacoum was different due to differences in their pharmacokinetics in wild rats. The new core-shell LC-MS/MS method is particularly well adapted for further exploration of diastereoisomers ratios in rodent and predatory wildlife biological samples in order to evaluate ecological consequences of actual baits, to explore new formulated baits with a good balance between efficacity (ability to kill rodents) and diastereoisomers persistence, and hopefully to mitigate exposure of non-target species.
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Validation of a new liquid chromatography- tandem mass spectrometry ion-trap technique for the simultaneous determination of thirteen anticoagulant rodenticides, drugs, or natural products.
Journal of Analytical Toxicology, 2010Co-Authors: Isabelle Fourel, Isabelle Goy-thollot, Christophe Hugnet, Philippe BernyAbstract:The purpose of this study was to develop and validate a liquid chromatography‐tandem mass spectrometry method for the identification and quantification of anticoagulant (anti-vitamin K orAVK) compounds, including rodenticides, drugs, and natural products because no published method could be found.The proposed method is based on ion-trap technology with electrospray ionization (ESI) and multiple reaction monitoring (MRM) technique. EachAVK is identified by means of its retention time, precursor ion, and two product ions. Plasma samples are extracted by liquid‐liquid partition onToxi-tube B ®.The method was validated on dog plasma and gave good results in terms of specificity, linearity, and percent recovery for the 14AVK tested (warfarin, acenocoumarol, bromadiolone, brodifacoum, chlorophacinone, coumatetralyl, dicoumarol, difenacoum, difethialone, Flocoumafen, fluindione, phenindione, and tioclomarol).The limits of detection ranged from 5 to 25 ng/mL. Intraday repeatability was good, but interday repeatability was more variable though still sufficient for our diagnostic purposes. The technique was successfully applied in a series of clinical investigations to demonstrate its applicability in various animal species and gave very high sensitivity and specificity results.
Qingfen Meng - One of the best experts on this subject based on the ideXlab platform.
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Rapid Simultaneous Screening and Detection of 12 Anticoagulant Rodenticides in Food by Ultra-performance Liquid Chromatography-Triple Quadrupole/Linear Ion Trap Tandem Mass Spectrometry
Food Analytical Methods, 2017Co-Authors: Xiaoqian Yang, Haitao Jiao, Qingfen MengAbstract:A rapid analytical method for the simultaneous screening and detection of 12 anticoagulant rodenticides in food samples was established based on modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) sample preparation method using an ultra-performance liquid chromatography-triple quadrupole/linear ion trap tandem mass spectrometry (UPLC-QTrap-MS/MS). Food samples were extracted and purified with modified QuEChERS method. The 12 anticoagulant rodenticides (warfarin, brodifacoum, difethialone, coumachlor, coumatetralyl, bromadiolone, chlorophacinone, difenacoum, diphacinone, pindone, valone, and Flocoumafen) and the internal standard (warfarin-D5) were separated within 6 min using an ACQUITY UPLC BEH-C18 column (1.7 μm, 2.1 mm × 50 mm) and gradient elution with the mobile phase consisting of 5 mM ammonium acetate formate buffer and acetonitrile. The multiple reaction monitoring-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scanning was employed for detection. The calibration curves were linear (R2 > 0.99) for all the compounds. The mean recoveries for the 12 analytes at three spiked levels (1× LOQ, 5× LOQ, and 10× LOQ) were in the range of 79.5–113.2% with RSDs of 1.8–13.2%.The limits of detection (LOD) for the 12 rodenticides ranged from 0.01 (warfarin) to 0.05 μg/kg (diphacinone). The limit of quantification (LOQ) for the 12 rodenticides was between 0.02 (warfarin) and 0.10 μg/kg (diphacinone). The developed method was more straightforward, less time and labor intensive, and more sensitive, selective, and accurate for screening multiple anticoagulant rodenticides, and it was successfully used in several poisoning cases.
Xiao-hong Chen - One of the best experts on this subject based on the ideXlab platform.
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Determination of five 4-hydroxycoumarin rodenticides in whole blood by high performance liquid chromatography with fluorescence detection
Se pu = Chinese journal of chromatography, 2007Co-Authors: Micong Jin, Xiao-hong ChenAbstract:A simple, accurate and sensitive method has been developed for the simultaneous determination of warfarin, coumatetralyl, bromadiolone, Flocoumafen and brodifacoum in whole blood by high performance liquid chromatography (HPLC) with fluorescence detection. The five 4-hydroxycoumarin rodenticides in whole blood were extracted by ethyl acetate, separated on XDB C,, column( 150 mm x 2. 1 mm, 5 [microm) by using the mobile phase consisting of methanol-0. 2% acetic acid aqueous solution (88: 12, v/v) at a flow rate of 0. 5 mL/min and detected with a variational time program for fluorescence wavelength. Each analyte was qualitatively determined with its fluorescence excitation spectrum, fluorescence emission spectrum and retention time being compared with those of the reference standard, and quantified with external calibration method. The linear range was 0. 01 - 10. 00 mg/L and the limit of quantification was 0. 01 mg/L except warfarin of which the corresponding results were 0. 05 - 10. 00 mg/L and 0. 05 mg/L. The recoveries were between 81% and 98% and the relative standard deviations (RSDs) were between 3. 8% and 8. 5%. This method can be used in the diagnosis of the clinical poisoned patients.
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Rapid determination of three anticoagulant rodenticides in whole blood by liquid chromatography coupled with electrospray ionization mass spectrometry.
Rapid communications in mass spectrometry : RCM, 2006Co-Authors: Micong Jin, Xiao-hong ChenAbstract:A rapid, sensitive and selective method for the simultaneous determination of bromadiolone, Flocoumafen and brodifacoum in whole blood using warfarin as internal standard (IS) by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC/ESI-MS) has been developed and validated. The target compounds were extracted from the whole blood with ethyl acetate and separated on an XDB C18 column (150 mm x 2.1 mm i.d. x 5 microm) by using a mobile phase consisting of 0.2% acetic acid/methanol (12/88, v/v) at a constant flow rate of 0.50 mL/min. The analytes were detected using negative ESI-MS in the selected ion monitoring (SIM) mode. The molecular ions [M-H]- of m/z 527, 541,523 and 307 were selected for the quantification for bromadiolone, Flocoumafen, brodifacoum and the IS, respectively. The calibration curves were linear (r2 > 0.995) in the concentration range of 0.50-100.00 ng/mL. The method showed a satisfactory sensitivity (0.05-0.5 ng/mL using 200 microL blood), precision (RSD < 11.9%), accuracy (recovery: 82.0-96.1%) and selectivity. This method was successfully applied to the determination of the analytes for the diagnoses of poisoned human beings and animals.
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High-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry for the determination of Flocoumafen and brodifacoum in whole blood.
Journal of applied toxicology : JAT, 2006Co-Authors: Micong Jin, Xiao-kun Ouyang, Xiao-hong ChenAbstract:A high-performance liquid chromatographic–tandem mass spectrometric (HPLC–MS–MS) assay was developed and validated to determine quantitatively Flocoumafen and brodifacoum in whole blood using warfarin as an internal standard (IS). Liquid–liquid extraction, using ethyl acetate, was used to isolate Flocoumafen, brodifacoum and the IS from the biological matrix. Detection was performed on a mass spectrometer by negative electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The calibration curves were linear (r2 > 0.998) in the concentration range of 0.1–100.0 ng ml−1 with a lower limit of quantification of 0.05 ng ml−1 for Flocoumafen, and 0.1 ng ml−1 for brodifacoum in whole blood. Intra-day and inter-day relative standard deviations (RSDs) were less than 8.0% and 10.8%, respectively. Recoveries of Flocoumafen and brodifacoum ranged from 78.0% to 83.7%. This assay can be used to determine trace Flocoumafen and brodifacoum in whole blood to investigate suspected poisoning of human and animals. Copyright © 2006 John Wiley & Sons, Ltd.
Oeesook Park - One of the best experts on this subject based on the ideXlab platform.
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total synthesis of Flocoumafen via knoevenagel condensation and intramolecular ring cyclization general access to natural products
Molecules, 2012Co-Authors: Jae Chul Jung, Oeesook Park, Jeremy Ricci, Mankil JungAbstract:The total synthesis and structure determination of cis- and trans-Flocoumafen was described. The key synthetic steps involve Knoevenagel condensation with p-methoxybenzaldehyde, in situ decarboxylation and intramolecular ring cyclization to construct the tetralone skeleton. Stereospecific reduction of the O-alkylated ketone 13 afforded good yield of precusor alcohol 5. Final coupling of alcohol 5 with 4-hydroxy-coumarin yielded Flocoumafen (1). Separation and structure determination of cis- and trans-Flocoumafen through 2D NMR analyses-assisted computer simulation techniques for the evaluation of anticoagulant activities are reported for the first time. This method is useful for generating the core tetralone skeleton of 4-hydroxycoumarin derivatives and provides a generalized access to various warfarin type anticoagulants.
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Simple synthesis and biological evaluation of Flocoumafen and its structural isomers
Journal of Chemical Sciences, 2010Co-Authors: Jae Chul Jung, Soyong Jang, Oeesook ParkAbstract:Simple synthesis and biological properties of Flocoumafen 1 and its structural isomers are described. The key synthetic strategies involve Knoevenagel condensation, Grignard reaction, intramolecular ring cyclization and coupling reaction. Flocoumafen 1 was easily separated into cis and trans forms using flash column chromatography. They were then evaluated for suppression of LPS-induced NO generation and anti-excitotoxicity in vitro . It was found that the trans-Flocoumafen was potent suppressor of NO generation with the concentration of 10 µM in vitro , while no significant effect for neurotoxicity in cultured cortical neurons.
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Synthesis of 4-hydroxycoumarin derivatives-1: An efficient synthesis of Flocoumafen
Archives of Pharmacal Research, 1995Co-Authors: Oeesook Park, Bong Suek JangAbstract:An anticoagulant, 4-hydroxy-3-[1,2,3,4-tetrahydro-3-(4-(4-trifluoromethylbenzyloxy)phenyl)-1-naphthyl]coumarin (Flocoumafen) was synthesized in 8 steps starting from phenylacetyl chloride and anisole. The key step in the synthesis involves the reaction of 3-(4-methoxyphenyl)-1-tetralol with 4-hydroxycoumarin to give 4-hydroxy-3-[1,2,3,4-tetrahydro-3-{4-methoxyphenyl}-1-naphthyl]coumarin.
Xiaoqian Yang - One of the best experts on this subject based on the ideXlab platform.
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Rapid Simultaneous Screening and Detection of 12 Anticoagulant Rodenticides in Food by Ultra-performance Liquid Chromatography-Triple Quadrupole/Linear Ion Trap Tandem Mass Spectrometry
Food Analytical Methods, 2017Co-Authors: Xiaoqian Yang, Haitao Jiao, Qingfen MengAbstract:A rapid analytical method for the simultaneous screening and detection of 12 anticoagulant rodenticides in food samples was established based on modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) sample preparation method using an ultra-performance liquid chromatography-triple quadrupole/linear ion trap tandem mass spectrometry (UPLC-QTrap-MS/MS). Food samples were extracted and purified with modified QuEChERS method. The 12 anticoagulant rodenticides (warfarin, brodifacoum, difethialone, coumachlor, coumatetralyl, bromadiolone, chlorophacinone, difenacoum, diphacinone, pindone, valone, and Flocoumafen) and the internal standard (warfarin-D5) were separated within 6 min using an ACQUITY UPLC BEH-C18 column (1.7 μm, 2.1 mm × 50 mm) and gradient elution with the mobile phase consisting of 5 mM ammonium acetate formate buffer and acetonitrile. The multiple reaction monitoring-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) scanning was employed for detection. The calibration curves were linear (R2 > 0.99) for all the compounds. The mean recoveries for the 12 analytes at three spiked levels (1× LOQ, 5× LOQ, and 10× LOQ) were in the range of 79.5–113.2% with RSDs of 1.8–13.2%.The limits of detection (LOD) for the 12 rodenticides ranged from 0.01 (warfarin) to 0.05 μg/kg (diphacinone). The limit of quantification (LOQ) for the 12 rodenticides was between 0.02 (warfarin) and 0.10 μg/kg (diphacinone). The developed method was more straightforward, less time and labor intensive, and more sensitive, selective, and accurate for screening multiple anticoagulant rodenticides, and it was successfully used in several poisoning cases.