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.

中文翻译：

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大鼠第二代抗凝血灭鼠剂地非噻酮的四种立体异构体的比较生物学特性：建立允许选择适当立体异构比的模型。

啮齿动物害虫种群的当前管理基于第二代抗凝灭鼠剂（SGAR）。这些分子（其中非地乙酮是其中的一部分）比第一代的分子效率要高得多。然而，这种效率有一个主要缺点，即SGARs具有组织持久性，会增加啮齿类动物对它们的暴露。根据其化学结构，地非噻酮具有四种立体异构体，其特异性抑制能力和药代动力学尚未被描述，可能对设计新型的生态友好型杀鼠剂有用。这项研究旨在研究大鼠中的四种地非噻酮立体异构体对大鼠抗凝靶酶（VKORC1）的抑制作用和药代动力学。我们表明，立体异构体都非常有效地抑制VKORC1活性，但对于E4-反式，E2-顺式，E1-反式和E3-顺式立体异构体，它们的初始半衰期分别为6.0小时，25.4小时，69.3小时和82.3小时。通过混合这些立体异构体中的某些，这些结果为开发生态友好型高效灭鼠剂开辟了道路。优先将E4-反式立体异构体（抑制VKORC1的效力高，肝脏半衰期相对较高）掺入地非噻酮灭鼠剂毒饵中，可以得到比目前市售的地非噻酮制剂更环保的产品。此外，我们提出了建模方法，通过调节理论AUC和啮齿动物死亡时产品的理论浓度，根据使用情况（非目标物种的存在，食物竞争等）帮助设计诱饵。害虫。从而，