GABAergic Neurotransmission and Toxicity 2: Macrocyclic Lactones

Abstract

The term “macrocyclic lactones” refers to a group of drugs typified by the avermectins and milbemycins. The former group includes abamectin, ivermectin, eprinomectin, doramectin, selamectin and emamectin benzoate, while the latter group comprises moxidectin and milbemycin oxime. They are widely used as antiparasitic agents in veterinary medicine, but ivermectin has been widely used in humans for the prophylaxis and treatment of filariasis, onchocerciasis and loiasis, in addition to other parasitic conditions; while more recently, moxidectin has been authorized for the treatment of onchocerciasis. These drugs have excellent safety profiles in routine toxicity tests at low-to-moderate dosages, but at high doses, neurotoxicity, typified by mydriasis, tremors, convulsions, ataxia and locomotor abnormalities and neurodegeneration, occurs. A specific strain of mouse, the CF-1 mouse, is more susceptible to the toxic effects of macrocyclic lactones than other strains. The CF-1 mouse is deficient in P-glycoprotein in the intestinal epithelium and brain endothelium when compared to non-sensitive animals, permitting greater intestinal absorption of these drugs and higher brain exposure. P-glycoprotein is an efflux pump encoded by the ABCB1 gene. Deficiency or disruption of this gene leads to higher toxicity of the macrocyclic lactones and other drugs in this mouse strain. Some dogs, notably but not exclusively the collie, have defective ABCB1 genes, leading to a greater susceptibility to the neurotoxic effects of some macrocyclic lactones. There is no evidence to suggest that these drugs may pose undue risks to humans when used at the recommended therapeutic doses.