MDR1 mutation and drug sensitivity
Research at Washington State University's College of Veterinary Medicine has demonstrated that a deletion mutation of the
MDR1 gene exists in ivermectin-sensitive collies.9 This deletion mutation produces a frame shift that generates a premature stop codon in the MDR1 gene, resulting in a severely
truncated, nonfunctional protein. Collies homozygous for the deletion (MDR1 mutant/mutant) exhibit ivermectin sensitivity,
while those that are heterozygous (MDR1 wild-type/mutant) may be sensitive to ivermectin. Homozygous wild-type are not sensitive
to ivermectin neurotoxicity. Many other herding breeds also harbor the mutation, including Australian shepherds, Shetland
sheepdogs, white German shepherds, and others. The prevalence of the MDR1 mutation in collies in the United States is fairly
high: about 22% are homozygous for the normal allele (normal), 42% are heterozygous (carrier), and 35% are homozygous for
the mutant allele (affected).10 In more recent studies, we have tested collies from France and Australia and have found the mutation at a similar frequency
(K.L. Mealey: Unpublished data, 2004).
A broad substrate affinity enables P-glycoprotein to transport a large number of structurally and functionally unrelated compounds.
The physiologic and pharmacologic consequence of P-glycoprotein drug transport, or lack thereof in affected dogs, depends
on the particular drug and tissue involved. Although P-glycoprotein has been identified in many body tissues, its functions
have been most well characterized in the brain and gastrointestinal tract. P-Glycoprotein expressed on the luminal border
of brain capillary endothelial cells protects the brain against a variety of compounds, including ivermectin, by pumping the
drug out of the endothelial cell and back into the bloodstream. P-Glycoprotein expressed on the luminal border of intestinal
epithelium pumps drugs from within the epithelial cell back into the intestinal lumen, thereby inhibiting systemic absorption
of many drugs.11
Animals that lack functional P-glycoprotein will experience greater oral bioavailability of certain drugs (P-glycoprotein
substrates) and accumulate higher concentrations of these drugs within brain tissue than normal animals (Table 1). For example, if the standard dose of cyclosporin A is administered orally to a dog with an MDR1 mutant/mutant genotype,
increased intestinal absorption may occur, resulting in significantly greater plasma concentrations of cyclosporin A. It is
important to note that many other drugs routinely used in veterinary patients may be substrates of P-glycoprotein (Table 1). In two recent reports, collies harboring the MDR1 mutation experienced extreme sensitivity to P-glycoprotein substrate
drugs including loperamide, doxorubicin, and vincristine.12,13 Sensitivity to avermectins other than ivermectin (i.e. selamectin, moxidectin, and milbemycin) in collies or other herding breeds has also been reported.14,15
Table 1: Selected Clinically Relevant Substrates of P-Glycoprotein
How can I identify affected dogs?
Pharmacogenetics, the study of genetic variation in drug response, offers the opportunity for truly individualized pharmacologic
therapy. The Veterinary Clinical Pharmacology Laboratory at Washington State University (firstname.lastname@example.org
http://www.vetmed.wsu.edu/depts-VCPL/) offers MDR1 genotyping for dogs. Owners and veterinarians can identify dogs that harbor the mutation before administering
potentially toxic drugs. Alternative drugs may be considered, or dosing adjustments can be made to decrease the risk of toxicosis.
Treating individuals according to their genotype fulfills the promise of pharmacogenetics.
The information for "On the Forefront" was provided by Katrina L. Mealey, DVM, PhD, DACVIM, DACVCP, Veterinary Clinical Sciences,
College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610.