TheABCB1‐1Δmutation is not responsible for subchronic neurotoxicity seen in dogs of non‐collie breeds following macrocyclic lactone treatment for generalized demodicosis

Abstract

P-glycoprotein (P-gp), encoded by the multiple drug resistance gene ABCB1 (also known as MDR1), is an integral component of the blood brain barrier crucial in limiting drug uptake into the central nervous system. Altered expression or function of P-gp, as seen in dogs of the collie lineage homozygous for the nt228(del4) mutation of the ABCB1 gene (ABCB1-1Delta), can result in potentially fatal neurotoxicosis, especially following administration of systemic macrocyclic lactones (SML). Occasionally, dogs from unrelated breeds develop subchronic signs of neurotoxicity when receiving SML to treat generalized demodicosis. It is possible that these dogs are heterozygous carriers of the ABCB1-1Delta mutation, resulting in decreased P-gp activity and central neurotoxicosis. Cheek swabs were collected from 28 dogs with generalized demodicosis that had shown subchronic signs of neurotoxicity following daily oral administration of ivermectin or other SML. Ten of these animals received concurrent systemic treatment with other confirmed or putative P-gp substrates. After DNA extraction, the relevant portion of the ABCB1 gene was amplified by polymerase chain reaction, and sequenced. Twenty-seven dogs were homozygous normal while one dog was heterozygous for the ABCB1-1Delta mutation. Therefore, with the exception of one dog, the observed neurotoxicity could not be attributed to the ABCB1-1Delta mutation. Possible explanations for the adverse reactions observed include pharmacological interactions (administration of SML with other P-gp substrates or inhibitors), excessively high doses, polymorphisms in P-gp expression, uncharacterized mutations in the ABCB1 gene or in another gene, or phenomena unrelated to the SML-P-gp interaction.

Rapid genotyping assays for the 4–base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs

“…11,12,24,25 Although the 4-bp deletion mutation in the canine MDR1 gene was often responsible for the hypersensitivity for the substrate drugs of P-gp especially in Collies, 20,22 it was reported that non-Collie dogs lacking this mutation were affected with subchronic neurotoxicity following administration ivermectin, milbemycin, and/or moxidectin for generalized demodicosis. 2 Recently, a novel insertion mutation of the canine MDR1 gene was identified in an ivermectinsensitive Border Collie, although the correlation between the insertion mutation and the ivermectin-sensitive phenotype in this dog was not clarified completely. 13 In human beings, at least 3 single nucleotide polymorphisms were found in the human MDR1 gene, 17 which may be related to abnormal sensitivity to multiple drugs.…”

Canine multi-drug resistance-1 mutation prevalence: A South African perspective

“…There is currently no specific safe and effective antidote available to treat this neurotoxicity and symptomatic and supportive treatment is indicated (Geyer & Janco 2012). Toxicity related to the mdr-1 gene mutation should not be confused with the subchronic neurotoxicity that could follow macrocyclic lactone administration in all dogs (Bissonnette et al 2008).…”

Treatment of canine demodicosis

“…Adverse neurological effects have also been reported in dogs of many different breeds with a normal MDR1 gene (Bissonnette and others 2009). In these dogs the signs usually occur late in the course of the therapy, are less severe and respond to a reduction of the ivermectin dose.…”