Toxicology of avermectins and milbemycins (macrocylic lactones) and the role of P-glycoprotein in dogs and cats

Abstract

The macrocyclic lactones (MLs) are parasiticides able to kill a wide variety of arthropods and nematodes. They have a high margin of safety for labeled indications, and ivermectin has become the best-selling antiparasitic in the world. Dogs of certain breeds and mixtures of those breeds have a defect in the ABCB1 gene (formerly MDR1 gene) that results in a lack of functional P-glycoprotein, which leads to accumulation of the MLs in the central nervous system and a higher risk of adverse effects when exposed. There is no specific antidote for ML toxicosis so the most important part of treatment is good supportive care.

Fig. 1

P-glycoprotein (P-gp) is a component of the blood brain barrier. P-gp actively transports substrates entering CNS endothelial cells back into the systemic circulation, thus preventing entry of substrates, such as ivermectin, into the parenchyma of the brain. Information from Refs.^,,– (Adapted from Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol 2008;18:159; with permission.)