Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms

The physiological and toxicological effects of xenobiotics are influenced by numerous factors including their chemical properties, route of exposure, absorption, distribution, metabolism, receptor binding, and excretion. Pharmacokinetic and toxicokinetic properties are often used to predict tissue concentrations and adverse effects, and therefore inform risk assessments. While anticoagulants rodenticides have been used to control pest rodents for decades, extant pharmacokinetic and toxicokinetic data for these compounds has principally been generated by studies using laboratory-bred or captive mammals and is scarce in non-target wildlife species, especially birds. Warfarin is by far the most studied anticoagulant rodenticide, likely because of its human therapeutic use. In general, anticoagulants are rapidly and principally absorbed in the intestine following ingestion. Metabolism is mediated by cytochrome P450 isozymes and ring hydroxylation also appears to be an important biotransformation step. Hydroxylated metabolites can further undergo conjugation with glucuronic acid prior to entering the systemic circulation, with potential enterohepatic recirculation. While the metabolite suite remains poorly described for most anticoagulant rodenticides, both the parent compounds and known metabolites appear to be largely bound to albumin while circulating. Hepatic metabolism is generally biphasic with a rapid initial phase and more prolonged terminal phase. Binding to vitamin K epoxide reductase sites, especially in liver tissue, exerts the common toxic effect of ‘anticoagulation’. The affinity of different anticoagulant compounds for the binding sites, and different biotransformation pathways for isomeric forms or second-generation compounds containing bromine, sulfur or fluorine likely contributes to some notable differences in the toxicity, metabolism and excretion of first versus second-generation compounds and coumarin versus indandione compounds. In general, second-generation anticoagulant rodenticides are more toxic with hepatic half-lives approximating 100–300 days, in contrast to first-generation compounds with hepatic half-lives in the range of 60 days or less. The indandiones tend to have the shortest hepatic persistence. Excretion of second-generation compounds tends to occur mostly through feces, while first-generation compound excretion is largely in urine. Additional data on transplacental and in ovo transfer, metabolism and elimination of anticoagulant rodenticides in non-target species would enhance hazard and risk evaluations.