On the Forefront: A new tool that detects ivermectin and other drug sensitivities in dogs

May 01, 2004

Dr. Katrina Mealey and Kenny, a collie with an MDR1 deletion mutation that makes him sensitive to certain drugs.
When Rollie, a 10-year-old male Shetland sheepdog, was found to have transitional cell carcinoma, Rollie's veterinarian wanted to make sure that he could be safely treated with doxorubicin. His veterinarian knew that Shetland sheepdogs are among the dog breeds that can be sensitive to such drugs as ivermectin and certain antineoplastic agents. This sensitivity is due to a deletion mutation of the multidrug resistance gene (MDR1), which testing at Washington State University's Clinical Pharmacology Laboratory can now detect. So Rollie's veterinarian sent a cheek brush sample for testing, and the results revealed that Rollie's MDR1 genotype is normal and that he could undergo doxorubicin chemotherapy.

Ivermectin sensitivity in collies

Ivermectin toxicosis in collies was first described in the 1980s.1-3 Clinical signs of ivermectin toxicosis include depression, ataxia, mydriasis, tremors, hypersalivation, coma, and other neurologic signs.2 Most mammals are protected from ivermectin's neurologic effects because the blood-brain barrier prevents access of ivermectin to the central nervous system. However, there is a subpopulation of collies and several other dog breeds that are exquisitely sensitive to the neurologic effects of ivermectin. Investigations in the late 1980s revealed that ivermectin is neurotoxic in some, but not all collies at doses a fraction of those required to cause toxicosis in other dogs.2 These investigations also revealed that affected collies accumulated high concentrations of ivermectin in brain tissue as compared with dogs that were not sensitive to ivermectin, suggesting that affected dogs lack a functional blood-brain barrier.2

The MDR1 gene

P-Glycoprotein, the product of the MDR1 gene, is a 170-kD, membrane-spanning, cell-surface protein that functions as a drug efflux pump.4,5 P-Glycoprotein was first identified more than 20 years ago in chemotherapeutic-drug-resistant tumor cells and is now known to be a principal cause of multidrug resistance in human and veterinary cancer patients. In tumor cells, P-glycoprotein functions as an ATP-dependent efflux pump, resulting in decreased intracellular drug accumulation and reduced cytotoxicity of a variety of anticancer agents.4,5

P-Glycoprotein is expressed not only in tumor cells but also in a variety of normal tissues, including renal tubular epithelium, canalicular surfaces of hepatocytes, adrenocortical cells, colonic and intestinal epithelium, brain capillary endothelial cells, and others.6 Consistent with P-glycoprotein's function as a transport pump, the expression of P-glycoprotein in nonneoplastic tissues suggests a normal physiologic role for P-glycoprotein mediating the export of potentially toxic xenobiotics from the body. Although the normal function of P-glycoprotein in many of these tissues has not been elucidated, a great deal is known about its role in the blood-brain barrier.

Experiments involving MDR1a (-/-) knockout mice provided the first evidence that P-glycoprotein played a role in the blood-brain barrier. Initial experiments involving ivermectin demonstrated that MDR1a (-/-) knockout mice were 50 to 100 times more sensitive to the adverse neurologic effects of ivermectin than mice with normal P-glycoprotein expression (wild-type mice).7 The concentration of ivermectin in brain tissue was 90 times higher in MDR1a (-/-) knockout mice than in wild-type mice. These results provide substantial evidence that P-glycoprotein transports ivermectin from the brain back into the peripheral circulation.

Further experiments in MDR1 knockout mice using other potentially neurotoxic drugs, including digoxin, ondansetron, loperamide, paclitaxel, vinblastine, and doxorubicin, yielded similar results.7,8 Drug concentrations in brain tissue from MDR1 knockout mice were substantially greater than concentrations in wild-type mice, and neurotoxicity was frequently observed in MDR1 knockout mice but not in wild-type mice.