Warfarin‐based rodenticides: Mode of action and mechanism of resistance

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Abstract
Warfarin and related substances have been in use as rodenticides for fifty years. They act by binding to the enzyme vitamin K 2,3‐epoxide reductase, thereby interrupting the cellular recycling of vitamin K. Vitamin K in its hydroquinone form is an essential cofactor for the synthesis of functional prothrombin and related blood‐clotting factors. The binding with the reductase is essentially irreversible, indicating these compounds have a prolonged half‐life in target tissues; 7–10 days for warfarin and congeners and over 100 days for the second generation rodenticides or ‘superwarfarins’ such as difenacoum, brodi‐facoum, and flocoumafen. Rat liver contains 1–2 nmole of enzyme per gram tissue which is a 4–5 fold overcapacity for maintaining effective vitamin K recycling. The use of warfarin as a rat poison has resulted in the natural selection of warfarin‐resistant rats. The resistance is inheritable. Two distinct warfarin resistance genotypes, Welsh and Scottish, have been identified, clearly differing in their biochemistry of vitamin K epoxide reductase. In the Welsh strain, resistance arises from an altered enzyme expressing reduced reactivity to warfarin, whereas the reductase from the Scottish strain is as sensitive as the normal enzyme, but the interaction with warfarin is now readily reversible. The altered enzyme leaves the Welsh rat in need of higher dietary vitamin K intake. The superwarfarins cope with the resistance by having their structures firmly bind with the altered enzymes. Reduced sensitivity to warfarin‐based rodenticides may also be pharmacokin‐etically based, arising from increased warfarin biotransformation. This mechanism may be responsible for resistance to some of the superwarfarins such as difenacoum. A third resistance mechanism may arise from an enhanced capacity to synthesize vitamin K from menadione, a commonly used additive in animal foods on farms. The choice of rodenticide in the case of warfarin resistance should be guided by the underlying mechanism of resistance.