Abstract
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.
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Notes
Equation used to model the liver concentration evolution in time of different mixes of difethialone stereoisomers. i is the index of each stereoisomer; f the fraction of each stereoisomer in the modelized mix; F the fraction of each stereoisomer in the experimental mix (F1 = 0.275, F2 = 0.225, F3 = 0.225, F4 = 0.275); d is the dose of difethialone to model; \(\mathrm{D}\) is the dose of difethialone used in our experimental plan (in mice \(D\) = 3.0 mg/kg, in rats \(D\) = 3.4 mg/kg);\({C}_{\Delta , i,24}\) is the average concentration obtained experimentally for the respective stereoisomer at 24 h and with the \(\mathrm{D}\) dose of difethialone; \({\lambda }_{i}\) is the decrease constant of the respective stereoisomer obtained experimentally with data between 24 and 168 h; t is the time variable that can take values between 24 and 168 h.
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Conceptualization: VL, EB, SL; methodology: AR, VL, AF, IF, SL; data curation: AR, SL; formal analysis and investigation: AR, VL, SL; writing—original draft preparation: AR, VL, SL; writing—review and editing: AR, VL, AF, HC, IF, EB, SL; funding acquisition: VL, HC; resources: VL; supervision: VL, SL.
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Rached, A., Lattard, V., Fafournoux, A. et al. 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 96, 535–544 (2022). https://doi.org/10.1007/s00204-021-03210-0
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DOI: https://doi.org/10.1007/s00204-021-03210-0