P-glycoprotein, encoded by the multidrug resistance gene MDR1, is an ATP-driven drug efflux pump which is
highly expressed at the blood-brain barrier of vertebrates. Drug efflux of macrocyclic lactones by P-glycoprotein is highly
relevant for the therapeutic safety of macrocyclic lactones, as thereby GABA-gated chloride channels, which are confined
to the central nervous system in vertebrates, are protected from high drug concentrations that otherwise would induce neurological
toxicity. A 4-bp deletion mutation exists in the MDR1 gene of many dog breeds such as the Collie and the Australian
Shepherd, which results in the expression of a non-functional P-glycoprotein and is associated with multiple drug
sensitivity. Accordingly, dogs with homozygous MDR1 mutation are in general prone to neurotoxicity by macrocyclic lactones
due to their increased brain penetration. Nevertheless, treatment of these dogs with macrocyclic lactones does not
inevitably result in neurological symptoms, since, the safety of treatment highly depends on the treatment indication, dosage,
route of application, and the individual compound used as outlined in this review. Whereas all available macrocyclic
lactones can safely be administered to MDR1 mutant dogs at doses usually used for heartworm prevention, these dogs will
experience neurological toxicity following a high dose regimen which is common for mange treatment in dogs. Here, we
review and discuss the neurotoxicological potential of different macrocyclic lactones as well as their treatment options in
MDR1 mutant dogs.
Dog, ivermectin, ivermectin-sensitive Collie, MDR1, milbemycin oxime, moxidectin, P-glycoprotein, pharmacogenetics
Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University of Giessen, Frankfurter Str. 107, 35392 Giessen, Germany.