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.
Dr. Katrina Mealey and Kenny, a collie with an MDR1 deletion mutation that makes him sensitive to certain drugs.
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
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.