Development of an Ecofriendly Anticoagulant Rodenticide Based on the Stereochemistry of Difenacoum.
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.
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Marlène
M
Damin-Pernik
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Bernadette
B
Espana
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Stéphane
S
Besse
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Isabelle
I
Fourel
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Hervé
H
Caruel
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Florence
F
Popowycz
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.).
Etienne
E
Benoit
USC 1233 INRA-VetAgro Sup, Veterinary School of Lyon, Marcy l'Etoile, France (M.D.-P., B.E., S.B., I.F., E.B., V.L.); Liphatech, Bonnel, Pont du Casse, France (M.D.-P., H.C.); and Laboratoire de Chimie Organique et Bio-organique, Institut National des Sciences Appliquées (INSA-Lyon), ICBMS-CNRS-UMR 5246, Villeurbanne Cedex, France (F.P.) Virginie.lattard@vetagro-sup.fr.
Virginie
V
Lattard
D015110:4-Hydroxycoumarins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000378:metabolism; D006207:Half-Life; D007536:Isomerism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012378:Rodenticides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014812:Vitamin K / Q000378:metabolism
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D012378:Rodenticides; D014812:Vitamin K; D004851:Epoxide Hydrolases; C012903:difenacoum