Tissue Distribution, Pharmacokinetics and Metabolism of Brodifacoum: a Superwarfarin

The absorption, tissue distribution, metabolism, and elimination of the anticoagulant rodenticide brodifacoum (BDF) was studied using a multi-dimensional quantitative and qualitative approach. Methods were developed in order to quantify the distribution and disposition of BDF in tissues, plasma, urine, and feces. Qualitative studies were carried out to determine the metabolism of BDF and to determine its route and rate of excretion. Quantitative analysis of BDF was carried out using LC-MS/MS with a triple quadrupole mass spectrometer, and the method was validated according to FDA guidelines. Qualitative analysis of BDF metabolites was carried out using rat liver microsomes and human hepatocytes combined with LC-MS/MS with a high resolution quadrupole time-of-flight mass spectrometer. Quantitative studies of BDF in rats and rabbits showed tissue accumulation in brain, liver, kidney, heart, and lung, with liver showing the highest concentrations. In the pharmacokinetic studies, plasma BDF reached a maximum concentration 24 hours after administration, and concentrations diminished over the next 4 days. Fecal elimination was highest during the first 24 hours after BDF administration and diminished rapidly thereafter. In vitro models of phase 1 and phase 2 metabolism as well as in vivo measurements of tissue, feces and urine following BDF administration showed no evidence of BDF metabolism.