Management of Rodent Populations by Anticoagulant Rodenticides: Toward Third-Generation Anticoagulant Rodenticides

Abstract

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.

Poisoning by Anticoagulant Rodenticides in Humans and Animals: Causes and Consequences

“…Their liver storage and their elimination are Poisoning -From Specific Toxic Agents to Novel Rapid and Simplified Techniques for Analysiskey factors, which determine a part of their eiciency and their persistence. The elimination pathway depends on the molecule and on its enantiomeric form [20]. For example, enantiomers of warfarin are eliminated diferently.…”

“…Therefore, commercial second-generation ARs are a mixture of two diastereoisomeric forms (1R,3R)(1S,3S)-isomers and (1R,3S)(1S,3R)-isomers with diferent pharmacokinetic properties. For each second-generation AR, there is systematically one diastereoisomeric form with a shorter half-life than the other one (Table 1) [20,27]. Proportion between stereoisomers in commercial baits is deined by regulatory documents.…”

“…Thus, secondary poisonings of wildlife associated with the use of second generation are more often reported. But the development of new ARs recently proposed is based on the stereochemistry of second-generation ARs with reduced persistence but equivalent toxicity might greatly decrease the level of secondary exposition [20].…”

“…Therefore, some recent research makes efort to implement a third generation of ARs which is based on the stereochemistry concept, which would be eicient against resistant strains of rodents and be less persistent and thus less involved in secondary poisoning [20,27].…”

The stereoisomerism of second generation anticoagulant rodenticides: a way to improve this class of molecules to meet the requirements of society?

“…On the other hand, SGAR molecules have two asymmetric carbons and each of them can be in R or S configuration . Thus, SGAR molecules exist as four stereoisomers with asymmetric carbons ( i.e ., C1 and C3) being in R/R, R/S, S/R or S/S configuration.…”