White Feet, Don’t Treat?

Oct 19, 2015 / Practitioner Updates

multi-drug resistance

Implications of MDR1 in Canine Cancer Patients

The traditional “white feet, don’t treat” adage for multi-drug resistance (MDR) defects or “ivermectin-related” sensitivity is not limited to collie-type dogs. MDR1 alterations (both mutations and upregulation) profoundly affect cancer treatment.

The ABCB1 (MDR1) gene codes for P-glycoprotein, a drug transport pump. P-glycoprotein has a major role in drug absorption, distribution (especially to the brain), metabolism, and excretion. Dogs with an MDR1 gene mutation have defective P-glycoprotein. This results in delayed excretion of drugs transported by the P-glycoprotein pump, making MDR1 mutant dogs susceptible to severe drug toxicity. High doses of ivermectin can cause neurologic toxicity in MDR1 mutant dogs, while low doses (e.g., heartworm prevention) are considered safe. Dogs that are homozygous for the MDR1 mutation (MDR1 mutant/mutant) are at highest risk although dogs that are heterozygous (MDR1 mutant/normal) can also have toxicity. Classically herding breeds are most at risk, with approximately 70 percent of collies affected. North American breeds with the highest percentage of affected dogs include collies, Australian/mini Australian shepherds, and Shetland sheepdogs. Other affected breeds include German shepherd, herding breed crosses, uncommon breeds (longhaired whippet, silken windhound), and even ~5 percent of mixed-breed dogs. Less than 5 percent of border collies are affected. Other P-glycoprotein substrates include acepromazine, butorphanol, and loperamide and these drugs should be used with caution in MDR1 mutant dogs.

In veterinary oncology the MDR1 mutation can contribute to increased chemotherapy toxicity in MDR1 mutant dogs. Dogs with P-glycoprotein deficiency (homozygous mutation) have impaired drug clearance and prolonged exposure to common chemotherapy drugs such as doxorubicin and vinca alkaloids (vincristine, vinblastine). Homozygous dogs are at risk of life-threatening adverse effects even at reduced drug doses. Heterozygous dogs are carriers and although risk may be modestly increased, the clinical impact is similar to wild type (normal MDR1) dogs.

Conversely, increased MDR1 (resulting in increased cellular P-glycoprotein drug pumps) in tumor cells can induce resistance to chemotherapy. As noted the gene name MDR1 derives from multi-drug resistance. Although controversial glucocorticosteroid-induced upregulation of P-glycoprotein is one proposed mechanism for the decreased efficacy of subsequent chemotherapy in dogs with lymphoma pre-treated with prednisone.

Prior to administration of P-glycoprotein drugs (chemotherapy and others) genotyping of at-risk breeds for MDR1 mutation status is recommended. A commercial blood or cheek swab test is available. Dogs with multicentric lymphoma should not be treated solely with long-term prednisone as it may result in a poorer outcome with subsequent traditional chemotherapy.

—Jackie Wypij, DVM, MS, DACVIM (Oncology)