Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats.
A dose-response curve for the hypoprothrombinemic effect of brodifacoum 3-[-3(4'-bromobiphenyl-4-yl) 1,2,3,4-tetrahydronaphth-1-yl] -4-hydroxycoumarin, was constructed using doses ranging from 0.1 to 0.33 mg/kg. Brodifacoum exhibited a remarkably steep dose-response curve. Brodifacoum failed to exhibit a dose-dependent effect on the degradation rate constant (kdeg) for prothrombin complex activity (PCA) after a PCA-synthesis-blocking dose of warfarin. Both phenobarbital pretreatment and SKF525A treatment altered to anticoagulant response to brodifacoum. Phenobarbital decreased the anticoagulant effect, whereas SKF525A increased it, suggesting that a substantial portion of brodifacoum-induced hypoprothrombinemia is mediated by brodifacoum itself rather than by metabolites. Finally, rats dosed orally with brodifacoum (0.2 mg/kg p.o.) were sacrificed in groups of 3-5 at various times up to 120 h after the dose. Brodifacoum was assayed in serum, small intestine, and liver by an HPLC method. Brodifacoum disappeared slowly from serum with a half-life of 156 h. Disappearance from small intestine was rapid, for 24 h, but intestinal levels began increasing from 24 to 72 h after the dose. Concentrations in liver were rapidly established, and exceeded serum concentrations by 20-fold. Brodifacoum levels in liver remained relatively constant for 96 h. Sustained liver concentrations after a single dose may partially account for brodifacoum's apparent potency relative to warfarin.
D015110:4-Hydroxycoumarins / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011516:Prothrombin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014859:Warfarin
D015110:4-Hydroxycoumarins; D014859:Warfarin; D011516:Prothrombin; C013418:bromfenacoum; D011335:Proadifen; D010634:Phenobarbital