The Bile Sequestrant Cholestyramine Increases Survival in a Rabbit Model of Brodifacoum Poisoning

Abstract

Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.

Continued Anticoagulant Rodenticide Exposure of Red‐tailed Hawks (Buteo jamaicensis) in the Northeastern United States with an Evaluation of Serum for Biomonitoring

“…Although all potential confounding factors relating to the nature of blood sample collection in the present study must be considered, trends in matched liver and serum concentrations could reflect agreement with overall SGAR toxicokinetic data in other species that show that both liver and serum levels rise and begin to decline rapidly soon after ingestion, with liver residues being much higher and persisting over a more prolonged time (Bachmann and Sullivan 1983; Huckle et al 1988; Woody et al 1992; Vandenbroucke et al 2008; Enouri et al 2015; Lindeblad et al 2018). Liver and serum levels of brodifacoum were significantly positively correlated, with the same bird having the highest concentrations of brodifacoum in both liver and serum, at 930 and 65 ng/g, respectively.…”

“…Data in laboratory rodents as well as in nonrodent mammals indicate that, in general, concentrations of ARs rise rapidly in serum or plasma as well as in liver soon after administration. However, the concentrations of ARs in serum or plasma are much lower than in liver, and these concentrations decline rapidly, with the highest levels occurring from 12 h to 3 d postadministration depending on species (Bachmann and Sullivan 1983; Huckle et al 1988; Woody et al 1992; Vandenbroucke et al 2008; Enouri et al 2015; Lindeblad et al 2018). Brodifacoum has been shown to be an exception to this pattern in laboratory mice (Vandenbroucke et al 2008) and rats (Bachmann and Sullivan 1983), displaying relatively slower disappearance from plasma and serum, respectively.…”

Adherence to Long-Term Follow-Up of Patients with Life-Threatening, Inhaled Synthetic Cannabinoids-Associated Coagulopathy in Chicago

“…For instance, Cohn et al (22) showed that treatment with oral cholestyramine, an FDA-approved, safe and efficacious, gut-restricted, anion-exchange resin indicated for the treatment of hypercholesterolemia, significantly reduced the half-life of chlordecone, a lipophilic organochlorine pesticide, in blood and fat of industrial workers that were exposed to substantial amounts of this toxin for several months. To this end, oral cholestyramine has been recently shown to reduce mortality of rabbits with acute brodifacoum poisoning (23).…”

Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?

“…Treatment with compounds that reduce recirculation, such as bile sequestrants, could be considered for use alone or in conjunction with ILE, to lower total body brodifacoum burden by accelerating clearance from the gut. In support of this, we showed that administration of the bile sequestrant cholestyramine to brodifacoum-poisoned rabbits increased survival to almost 100% [ 38 ]. Approaches that utilize other scavengers to sequester circulating brodifacoum, or reduce its binding to serum albumin, allowing for increased redistribution to the liver, should be considered.…”