Metabolic and Toxicological Studies on the Anticoagulant Rodenticide, Flocoumafen

Veenstra, G. E.; Owen, D.E.; Huckle, Keith R.

doi:10.1007/978-3-642-74936-0_32

Cited by 11 publications

(6 citation statements)

References 5 publications

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“…, 1989b). In beagle dogs, 8% of an administered flocoumafen dose of 0.4 mg/kg could be found in the liver for 43 weeks (Veenstra et al. , 1991).…”

Section: Discussionmentioning

confidence: 99%

“…It took about 100 days for flocoumafen to disappear from liver tissue in this bird species (Huckle et al, Pharmacokinetics of mice after single oral administration 443 1989b). In beagle dogs, 8% of an administered flocoumafen dose of 0.4 mg ⁄ kg could be found in the liver for 43 weeks (Veenstra et al, 1991). The half-life in rat liver is reported to be 7-10 days for warfarin, which contrasts with half-lives exceeding 100 days for second-generation anticoagulants (Thijssen, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Vandenbroucke

Bousquet‐mélou

Backer

et al. 2008

Vet Pharm & Therapeutics

129

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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.

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“…, 1989b). In beagle dogs, 8% of an administered flocoumafen dose of 0.4 mg/kg could be found in the liver for 43 weeks (Veenstra et al. , 1991).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Vandenbroucke

Bousquet‐mélou

Backer

et al. 2008

Vet Pharm & Therapeutics

129

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show abstract

“…Based on these results, oral vitamin K substitution was discontinued after approximately 6 wk. Our data suggest that the elimination half‐life of this superwarfarin may be considerably shorter in humans (approximately 6.7 d in our patient) than the 220 d reported in rodents (4) and underline the benefit of determining flocoumafen serum concentrations in affected patients to provide a rational basis for the duration of vitamin K substitution and adequate follow‐up intervals.…”

Section: Further Course and Discussionmentioning

confidence: 46%

“…This enzyme recycles vitamin K 2,3‐epoxide to vitamin K hydroquinone, the cofactor of γ‐glutamyl carboxylase, thereby preventing γ‐carboxylation of the vitamin K‐dependent clotting factors II, VII, IX, and X (2). Superwarfarins are not only approximately 100‐fold more potent than warfarin but also have a considerably longer half‐life varying from 16 to 220 d compared with 37 h for warfarin (3, 4). These rodenticides are available without restrictions and are widely used in both urban and rural areas.…”

mentioning

confidence: 99%

Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen

Boettcher¹,

Wacker²,

Moerike

et al. 2010

European Journal of Haematology

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A 28 year-old heretofore healthy woman was transferred to our hospital with a two-month history of recurring episodes of bleeding. Administration of vitamin K and prothrombin complex concentrates in the transferring hospital had only temporarily corrected both the markedly elevated international normalized ratio (INR) and the prolonged activated partial thromboplastin time (aPTT). The patient's medical and family history revealed no reason for these abnormalities. Our laboratory analyses revealed a sustained deficiency of vitamin K-dependent clotting factors. Presence of an acquired inhibitor of clotting factors was excluded. Thus we suspected, intoxication with an anticoagulant rodenticide. Liquid chromatography-mass spectrometry (LC-MS/MS) revealed pharmacologically active concentrations of flocoumafen, a rodenticide belonging to the superwarfarin family, in the patient's serum. While the long elimination half-life of superwarfarins is well described in rodents, information on pharmacokinetics in humans is not yet available. Therefore, patient management was not limited to prolonged administration of vitamin K, but also included repeated measurements of flocoumafen serum levels. During follow-up visits, clotting tests remained normal and flocoumafen levels gradually decreased, reaching the limit of quantification after 48 days. Based on the repeated measurements of flocoumafen serum levels, a half-life of 6.7 days was estimated in our patient, which is in clear contrast to the 220 days reported in rodents. Thus, monitoring flocoumafen serum concentrations in affected patients may provide a rational basis for the duration of vitamin K substitution and adequate follow-up intervals.

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“…Eight urinary metabolites were detected after percutaneous exposure to 14 C-flocoumafen but represented a small proportion of the total dose, with most excretion occurring in the feces as unchanged flocoumafen (Huckle and Warburton 1986 cited by Eason and Wickstrom (2001)). Veenstra et al (1991) found retention of about 8% of an administered flocoumafen dose of 0.4 mg/kg in the liver of beagle dogs 300 days after dosing. When oral 14 C-flocoumafen doses of 0.02 mg/kg or 0.1 mg/kg body weight were given to rats, once weekly for up to 14 weeks, approximately one-third of each weekly low dose was eliminated through the feces within 3 days, mostly within the first 24 h. At the higher dose, the fecal excretion ranged from 18% after the first dose to 59% after the 10th dose (Huckle et al 1988).…”

Section: Flocoumafenmentioning

confidence: 94%

Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms

Horak¹,

Fisher

Hopkins

2017

Emerging Topics in Ecotoxicology

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Metabolic and Toxicological Studies on the Anticoagulant Rodenticide, Flocoumafen

Cited by 11 publications

References 5 publications

Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen

Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms

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