Abstract
Difenacoum, an antivitamin K anticoagulant, has been widely used as rodenticide to manage populations of rodents. Difenacoum belongs to the second generation of anticoagulant, and, as all the molecules belonging to the second generation of anticoagulant, difenacoum is often involved in primary poisonings of domestic animals and secondary poisonings of wildlife by feeding contaminated rodents. To develop a new and ecofriendly difenacoum, we explored in this study the differences in properties between diastereomers of difenacoum. Indeed, the currently commercial difenacoum is a mixture of 57% of cis-isomers and 43% of trans-isomers. Cis- and trans-isomers were thus purified on a C18 column, and their respective pharmacokinetic properties and their efficiency to inhibit the coagulation of rodents were explored. Tissue persistence of trans-isomers was shown to be shorter than that of cis-isomers with a half-life fivefold shorter. Efficiency to inhibit the vitamin K epoxide reductase activity involved in the coagulation process was shown to be similar between cis- and trans-isomers. The use of trans-isomers of difenacoum allowed to drastically reduce difenacoum residues in liver and other tissues of rodents when the rodent is moribund. Therefore, secondary poisonings of wildlife should be decreased by the use of difenacoum largely enriched in trans-isomers.
Highlights
Anticoagulant rodenticides (ARs) are used worldwide since the 1940s to control infestations of rats and mice, which cause important agricultural and structural damage and are associated with public health issues
Difenacoum belongs to the second generation of anticoagulant, and, as all the molecules belonging to the second generation of anticoagulant, difenacoum is often involved in primary poisonings of domestic animals and secondary poisonings of wildlife by feeding contaminated rodents
Vitamin K hydroquinone is the essential cofactor for the g-glutamyl carboxylase, which catalyzes the post-translational modifications of the clotting factors II, VII, IX, and X and other vitamin K–dependent proteins (Suttie, 1985; Furie and Furie, 1988)
Summary
Anticoagulant rodenticides (ARs) are used worldwide since the 1940s to control infestations of rats and mice, which cause important agricultural and structural damage and are associated with public health issues. The death of rodents occurs 3–7 days after consumption of baits. The first commercial rodenticide was dicoumarin, replaced a couple of years later by warfarin, a more efficient molecule (Hadler and Buckle, 1992). These products with coumatetralyl, chlorophacinone, and other molecules developed from 1950s compose the first generation of ARs (FGARs), which require multiple ingestions to cause death of rodents (Rattner et al, 2014). ARs acting as VKORC1 inhibitors stop the vitamin K–dependent clotting factor activation, impairing the coagulation function, and lead to the death of rodents by hemorrhages
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