Difethialone
(Synonyms: 噻鼠灵) 目录号 : GC49750
An anticoagulant rodenticide and a vitamin K antagonist
Cas No.:104653-34-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Difethialone is an anticoagulant rodenticide and a vitamin K antagonist.1 It binds to vitamin K epoxide reductase (VKOR; Kis = 0.04 and 0.05 µM for the wild-type and VKORY139F enzyme, respectively). Difethialone is toxic to mice (LD50 = 1.29 mg/kg).2 Formulations containing difethialone have been used in the control of rodent pest populations.
1.Hodroge, A., Longin-Sauvageon, C., Fourel, I., et al.Biochemical characterization of spontaneous mutants of rat VKORC1 involved in the resistance to antivitamin K anticoagulantsArch. Biochem. Biophys.515(1-2)14-20(2011) 2.Vandenbroucke, V., Bousquet-Melou, A., De Backer, P., et al.Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administrationJ. Vet. Pharmacol. Ther.31(5)437-445(2008)
| Cas No. | 104653-34-1 | SDF | Download SDF |
| 别名 | 噻鼠灵 | ||
| Canonical SMILES | O=C1SC2=C(C(O)=C1C3C4=CC=CC=C4CC(C3)C5=CC=C(C6=CC=C(C=C6)Br)C=C5)C=CC=C2 | ||
| 分子式 | C31H23BrO2S | 分子量 | 539.5 |
| 溶解度 | Chloroform: slightly soluble,Methanol: slightly soluble | 储存条件 | -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8536 mL | 9.2678 mL | 18.5357 mL |
| 5 mM | 0.3707 mL | 1.8536 mL | 3.7071 mL |
| 10 mM | 0.1854 mL | 0.9268 mL | 1.8536 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Comparative pharmacokinetics of Difethialone stereoisomers in male and female rats and mice: development of an intra- and inter-species model to predict the suitable formulation mix
Arch Toxicol 2022 Feb;96(2):535-544.PMID:35075517DOI:10.1007/s00204-021-03210-0.
The ecotoxicity of anticoagulants used for rodent pests' management is a major concern, particularly with second generation anticoagulants, which are more persistent in the body of rodents and therefore more likely to cause secondary exposure in their predators. One of the solutions envisaged to mitigate this risk is to use stereoisomers of these anticoagulants, each of which has particular pharmacokinetics. However, the few studies published to date have considered only one species and one sex. Here, we study the pharmacokinetics of the 4 stereoisomers of 3.4 mg/kg of Difethialone in rats (Rattus norvegicus) and 3 mg/kg in mice (Mus musculus) in both sexes and propose a model to choose the optimal stereoisomer efficacy/ecotoxicity mixture for the management of all these animals. Our results show that while the most persistent stereoisomer (E3-cis) is common to both species and sexes, the pharmacokinetics of the other stereoisomers show marked differences between sexes and species. Thus, the area under curve (AUC) of E4-trans in male rats is four times lower than in females or mice, making it a priori unusable in male rats. Conversely, our modeling seems to show that the E1-trans stereoisomer seems to offer the best compromise AUC persistence. In conclusion, we highlight that studies on anticoagulants must necessarily integrate research on the effect of gender and species both on efficacy and with regard to the ecotoxicity of these molecules.
Comparative biological properties of the four stereoisomers of Difethialone, a second-generation anticoagulant rodenticide, in rats: development of a model allowing to choose the appropriate stereoisomeric ratio
Arch Toxicol 2020 Mar;94(3):795-801.PMID:32047980DOI:10.1007/s00204-020-02662-0.
The current management of rodent pest populations is based on second-generation anticoagulant rodenticides (SGAR). These molecules, of which Difethialone is part, are much more efficient than the first generation. Nevertheless, this efficiency comes with a major drawback, SGARs are tissue persistent that increases the exposure of rodent predators to them. According to its chemical structure, Difethialone has four stereoisomers, whose specific inhibition potency and pharmacokinetic have never been described and might be useful to design new eco-friendly rodenticides. The study aimed to investigate the ability to inhibit anticoagulant target enzyme (VKORC1) and the pharmacokinetics in rats of the four Difethialone stereoisomers in rats. We show that stereoisomers are all highly efficient to inhibit VKORC1 activity, but they have distinct initial half-life with 6.0 h, 25.4 h, 69.3 h, and 82.3 h for, respectively, E4-trans, E2-cis, E1-trans, and E3-cis stereoisomer. These results open the way of the development of eco-friendly and efficient rodenticide by mixing some of these stereoisomers. Preferential incorporation of the E4-trans stereoisomer (high inhibitory VKORC1 potency, relatively shorter liver half-life) into Difethialone rodenticides baits might result in a more eco-friendly product than current commercially available Difethialone formulations. In addition, we put forward modelling to help design bait according to the circumstance of use (presence of non-target species, food competition, etc.) by modulating the theorical AUC and and the theorical concentration of the product at the death of the rodent pest. Thus, this modeling might allow to diminish the use of laboratory animal in assay.
Enantiomeric fraction evaluation of the four stereoisomers of Difethialone in biological matrices of rat by two enantioselective liquid chromatography tandem mass spectrometry methods: Chiral stationary phase or derivatization
J Chromatogr A 2020 May 10;1618:460848.PMID:31932088DOI:10.1016/j.chroma.2019.460848.
The need for the control of rodent populations with anticoagulant rodenticides remains actual, and enantioselective analytical methods are mandatory to understand ecotoxicity issues of those chiral pesticides. This study presents two enantioselective methods to achieve the residue levels and differentiated persistence of the four stereoisomers of Difethialone (called in this work E1-trans, E2-cis, E3-cis and E4-trans), which is one of the most toxic second generation anticoagulant rodenticide. Their enantiomeric fraction evaluation in biological matrices of rats was determined by two LC-MS/MS methods. The first one (chiral-LC-MS/MS) combined a chiral column employed in reversed-phase mode (with acetonitrile-water mobile phase) to be compatible with mass spectrometry detection. The second one was also a LC-MS/MS method but with a reversed phase column after a derivatization step with (1S)-(-)-camphanic chloride. Extraction process combined Solid-Liquid extraction and sorbent cartridges. The methods were fully validated. The chiral column was chosen as a reference method for our laboratory because it was quicker and cheaper, and enantioresolution and sensitivity were better. This chiral-LC-MS/MS method was used to measure the enantiomeric fraction of the four stereoisomers of Difethialone in rodent biological matrices (liver, plasma, blood and feces) of female rats treated with 3.5 mg/kg of Difethialone. The results showed that metabolism is not the same for all the stereoisomers: cis-E3-difethialone was the most persistent, and E4-trans-difethialone was the most quickly eliminated. This chiral-LC-MS/MS method will be used to study the pharmacokinetics of the four stereoisomers of Difethialone, and for ecotoxicological surveillance to evaluate the specific persistence of each stereoisomer of Difethialone in case of secondary exposure of wildlife non-target species.
Separation and Quantification of Superwarfarin Rodenticide Diastereomers-Bromadiolone, Difenacoum, Flocoumafen, Brodifacoum, and Difethialone-in Human Plasma
J AOAC Int 2020 Jun 1;103(3):770-778.PMID:33241367DOI:10.1093/jaoacint/qsaa007.
Background: Superwarfarins, second-generation long-acting anticoagulant rodenticides, are 4-hydroxycoumarin analogues of warfarin that contain a large hydrophobic side chain. These compounds contain two chiral centers and are synthesized for commercial use as two pairs of diastereomer. Objective: To support studies of superwarfarin pharmacokinetics and other efforts to improve clinical care for poisoning victims, a quantitative assay was developed for the measurement of diastereomer of bromadiolone, difenacoum, flocoumafen, brodifacoum, and Difethialone in human plasma. Method: Based on ultrahigh-pressure liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), this method was validated according to U.S. Food and Drug Administration (FDA) guidelines. Sample preparation involved simple protein precipitation followed by reversed phase UHPLC, which resolved all five pairs of cis/trans diastereomer in less than 10 min. Superwarfarins were measured using negative ion electrospray followed by selected-reaction monitoring on a triple quadrupole mass spectrometer. Results: Calibration curves covered 3-4 orders of magnitude with linear regression coefficients of >0.999. The lower limits of quantitation were from 0.013 to 2.41 ng/mL, and intra-day and inter-day accuracy and precision coefficients of variation were <12%. Conclusions: A 10-min UHPLC-MS/MS assay was developed and validated for the separation and quantitative analysis of the pairs of diastereomer of five superwarfarins in human plasma. Highlights: This method was used to identify and measure superwarfarins and their cis/trans diastereomers in plasma obtained from patients treated for coagulopathy following consumption of contaminated synthetic cannabinoid products.
Response of predominant rodent borne diseases to Difethialone anticoagulant rodenticide under laboratory conditions
J Egypt Soc Parasitol 2010 Dec;40(3):631-40.PMID:21268533doi
Susceptibility level to Difethialone 0.0025% anticoagulant rodenticide by bioassay method were studied (during 2009 & 2010) to the Norway rat Rattus norvegicus and the roof rat Rattus rattus trapped from Giza and Menoufia Governorates (G) where anticoagulant rodenticides were used to control rodents for long periods. Complete mortality was obtained for both species at two Governorates within 3 days no-choice feeding test period, indicated to be susceptible to Difethialone. The bait consumption and corresponding active ingredient intake was more in R. rattus than R. norvegicus. The mean intake values for R. rattus were 3.1 & 2.29 mg/kg at Giza G and 2.63 & 2.65 mg/kg at Menoufia G for males and females and for R. norvegicus 1.93 & 2.29 mg/kg at Giza and 2.14 & 2.09 mg/kg at Menoufia for males and females, respectively. Within 2 days no-choice feeding test period, Difethialone caused mortality ranged between 70-80% for both species. The higher intake values of active ingredient for died animals was recorded for R. rattus males at Giza G (2.23 mg/kg), while the lower value was recorded for R. norvegicus females of at Menoufia G (1.37 mg/kg). Within one-day no-choice feeding test period, Difethialone caused mortality ranged between 60-70% for R. norvegicus and 50-60% to R. rattus. The higher intake values for died animals were recorded for R. rattus males at Giza G (1.45 mg/kg), while the lower value was recorded for R. norvegicus males at Giza (0.75 mg/kg).