Absorption and elimination of [14C]-Dicoumarol in goats

Authors: CHAKRABARTY, SHUBHASHIS - Orise Fellow; Smith, David

Submitted to: American Society of Animal Science
Publication Type: Proceedings
Publication Acceptance Date: 5/3/2017
Publication Date: 6/20/2017
Citation: Chakrabarty, S., Smith, D.J. 2017. Absorption and elimination of [14C]-Dicoumarol in goats. Proceedings of Western Section American Society of Animal Science. 68:188-191.

Interpretive Summary: Dicoumarol is a natural toxin that causes sweet clover disease in cattle. Because dicoumarol is a very strong anti-coagulant, intoxicated cattle are susceptible to internal hemorrhage and possible death. The toxin is typically formed by fungi that are present in low quality hays or silages containing sweet clover. Although dicoumarol was discovered to be a cattle toxin over 70 years ago, and though it has been used as a human drug, its absorption, distribution, metabolism, and excretion has never been described in ruminant animals. The goal of this research project was to determine the extent of dicoumarol absorption and the rate at which it is eliminated from blood and accumulates in urine of goats. On average, over one-half of the non-toxic dose (5 mg/kg body weight) was absorbed into the bloodstream within 2 hours of dosing; in contrast, the half-life of elimination from blood averaged over 15 hours. By 72 hours of the study, less than 20% of the dose had been eliminated in urine. These results suggest that in ruminants, dicoumarol will accumulate after repeated oral exposures. Such accumulation could cause blood levels of the toxin to exceed toxic thresholds in naturally exposed animals. The data also suggest that edible tissues of animals with recent dicoumarol exposures could contain residues of potential concern.

Technical Abstract: Dicoumarol is a well-known toxic anti-coagulant which contributes to sweet clover poisoning in exposed cattle. To our knowledge, ADME studies of dicoumarol have never been conducted in ruminant animals, which are the natural targets of dicoumarol poisoning. Three healthy wether goats (31 ± 7 kg) were orally administered a single bolus dose of 5 ± 0.02 mg/kg of [14C]-dicoumarol, while one goat was used as a control. Blood, urine and feces were collected for a 72-h period after dosing. At 72 h, goats were euthanized and adipose tissue, bile, blood, bone, brain, gastrointestinal contents, gastrointestinal tissue, heart, lungs, liver, kidneys, pancreas, skeletal muscle, skin, spleen, and thyroid were collected for the analysis of total radioactive residues. The cumulative excretion of radioactive residues in urine represented 18.4 ± 2.4% of the total dose by 72 h. Peak levels of radioactive residues occurred at 12-18 h in urine; at 72 h, urinary radioactivity represented 2.4 ± 0.9 µg/g of dicoumarol equivalents. Blood levels of total radioactive residues peaked at 5.1 ± 2 µg/g (Cmax) of dicoumarol equivalents at 5.97 ± 1.27 h (tmax). The half-life of radioactive residue absorption was 1.81 ± 0.75 h; the half-life of elimination from blood was 14.16 ± 3.0 h. At 72 h radioactivity in blood remained at 0.22 ± 0.04 µg/g dicoumarol equivalents. Evidence for the biliary elimination of dicoumarol (and/or its metabolites) was present with 72 h bile containing 1.56 ± 0.29 µg/g of dicoumarol equivalents. These preliminary results indicate that dicoumarol is rapidly absorbed, and slowly eliminated in goats.