P-glycoprotein works in concert with cytochrome P450 3A in enterocytes to prevent the oral absorption of many drugs. It is also expressed on renal tubular cells, bile canalicular cells, and brain capillary endothelial cells, functioning as part of the blood-brain barrier and apparently playing a role in renal and biliary drug excretion. A deletion mutation of the mdr (multidrug-resistant) gene, which codes for a P-glycoprotein, has been demonstrated in ivermectin-sensitive collie dogs. This may contribute to the susceptibility to toxicity of collie dogs and related breeds from chemotherapy drugs and digoxin. Dogs with this gene deletion also have increased brain concentrations of ivermectin, moxidectin, loperamide, and corticosteroids. The mdr gene deletion has been documented in 10 dog breeds, being widespread in collie dogs (30% homozygous and 40% heterozygous) and present at a much lower frequency in herding breeds of collie lineage (eg, Shetland sheepdog, Old English sheepdog, and Australian sheepdog). It has not been found in border collie, bearded collie, or Australian cattle dogs. Adverse effects from ivermectin and other P-glycoprotein substrate drugs at dosages that are safe in normal dogs are seen in dogs homozygous for the gene deletion. In heterozygous dogs, toxicity may be seen when substrate drugs are given at increased dosages (eg, daily ivermectin for treatment of demodicosis). Rather than adhering to the old adage "White feet, don't treat," thereby withholding drugs that might be ideal for the situation, it is recommended that the genotype of dogs from affected breeds be determined via a simple test to see instead whether it is safe to treat the individual dog.
COMMENTARY: This article describes one of the true "ah-ha" moments in scientific discovery-the gene-deletion mutation responsible for drug hypersensitivities in collies and other herding breeds. A simple and available genetic test can now screen for the mutation and provide veterinarians and owners the peace of mind of knowing whether they can administer macrolides and other drugs to an individual dog. Visit www.vetmed.wsu.edu/depts-vcpl for further information on submitting test samples, susceptible breeds, and problem drug lists.
Pharmacogenetics: It's not just about ivermectin in collies. Dowling P. CAN VET J 47:1165-1168, 2006.