Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Abstract

The first aim of the study was to investigate the pharmacokinetics of eight anticoagulant rodenticides (brodifacoum, bromadiolone, chlorophacinone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) in plasma and liver of the mouse after single oral administration. Eight groups of mice dosed orally with a different anticoagulant rodenticide in a dose equal to one-half the lethal dose 50 (LD(50)), were killed at various times up to 21 days after administration. The eight anticoagulant rodenticides were assayed in plasma and liver by an LC-ESI-MS/MS method. Depending on the compound, the limit of quantification was set at 1 or 5 ng/mL in plasma. In liver, the limit of quantification was set at 250 ng/g for coumatetralyl and warfarin and at 100 ng/g for the other compounds. The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. Coumatetralyl, a first-generation product, had a plasma elimination half-life of 0.52 days. Brodifacoum, a second-generation product, showed a plasma elimination half-life of 91.7 days. The elimination half-lives in liver varied from 15.8 days for coumatetralyl to 307.4 days for brodifacoum. The second aim of the study was to illustrate the applicability of the developed method in a clinical case of a dog suspected of rodenticide poisoning.

Development of an Ecofriendly Anticoagulant Rodenticide Based on the Stereochemistry of Difenacoum

“…However this increased persistence led to molecules with excessive half-lives while they kill rodents in only 3 to 7 days. For example, half-life of brodifacoum has been reported as being 307 days in mice (Vandenbroucke et al, 2008). While these molecules have been used without any report of cases of secondary poisoning for more than 30 years after the beginning of their marketing (Vandenbroucke et al, 2008), (Kaukeinen, 1982), the ecological impact of these molecules on wildlife is now obvious.…”

“…For example, half-life of brodifacoum has been reported as being 307 days in mice (Vandenbroucke et al, 2008). While these molecules have been used without any report of cases of secondary poisoning for more than 30 years after the beginning of their marketing (Vandenbroucke et al, 2008), (Kaukeinen, 1982), the ecological impact of these molecules on wildlife is now obvious. In spite of this obvious ecological impact, there has been no improvement of these AR molecules since the patent of difethialone in 1986.…”

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

“…There is a great discrepancy between tissue persistence of irst generation and second generation of ARs. First-generation molecules have tissue persistence of few days while the second generation has tissue persistence of few weeks [26]. This point is a major concern for AR ecotoxicity.…”

“…They depend on the used active ingredient [26,83]. Historically, second-generation ARs had been designed to be more persistent and toxic on resistant strain.…”

Comparison of warfarin sensitivity between rat and bird species

“…These second-generation warfarins are called "superwarfarins," and include brodifacoum, bromadiolone, and difethialone. The target molecule of a superwarfarin and the mode of action is the same as those of the first-generation drugs, but superwarfarins have a generally prolonged half-life in the body (Vandenbroucke et al, 2008). After the increase of second-generation anticoagulant production in the marketplace, primary-and secondary-poisoning incidents from these anticoagulants in birds have drastically increased (Albert et al, 2009;Walker et al, 2008;Johnston et al, 2005;Eason et al, 2002;Dowding et al, 1999;Empson and Miskelly, 1999;Howald et al, 1999;Stone et al, 1999), even though one advantage of warfarin as a rodenticide was its relatively safety for non-target animals.…”