Ivermectin Sensitity/MDR1 Mutation

The publication "Breed distribution and history of canine mdr1-1delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage" (Proc. Natl. Acad. Sciences, 2004, vol. 101, pp 11725-11730 www.pnas.org/cgi/reprint/101/32/11725) which was submitted early April 2004 states over 200 border collies were tested and zero were found with the mutation that causes ivermectin sensitivity. When I contacted the people at WSU performing the DNA test a few months back, thus far they have found no purebred border collies with this mutation and had only heard unsubstantiated rumours of ones in Europe with the mutation. In addition, dogs with this mutation will be sensitive to ALL heartworm meds on the market in addition to other medications. This is from the American Working Collie Association (where the sensitivity is an issue). So-called "ivermectin" sensitivity is actually sensitivity to a broad class of compounds due to a basic defect in the blood-brain barrier. Normal dogs are protected from acute and often fatal neurotoxic doses when these compounds are administered as pharmaceuticals (including ivermectin) by P-glycoprotein, an ATP-dependent drug transporter that moves a broad spectrum of substrates across several tissue borders throughout the body. The normal gene encoding for P-glycoprotein is MDR1. Anti-helminthic pharmaceuticals that are P-glycoprotein substrates include the family of compounds known as macrocyclic lactones. These compounds exert their anti-helminthic properties by causing neurotoxic doses in a number of invertebrates (including helminths and arthropods) by potentiating ligand-gated chloride ion channels in the peripheral nervous system. Generations of macrocyclic lactones known as avermectins have been developed for veterinary use, decreasing their toxic side effects to normal animals (without the mdr1-1Ä mutation). These compounds include: ivermectin, milbemycin oxime, moxidectin, selamectin, and doramectin. Given the mechanism for toxicity, there is no reason to consider milbemycin oxime safer for dogs with the mdr1-1Ä mutation than ivermectin. The monthly oral dose of both ivermectin and milbemycin oxime has been administered for heartworm prophylaxis to Collies homozygous for mdr1-1Ä without incident and both have been shown to have similar pharmaceutical margins of safety in sensitive Collies (Tranquilli et al. 1991).