Collies, their crosses, other herding breeds, and other mixed breed dogs may possess a mutation in a gene that produces the protein, P-glycoprotein. P-glycoprotein is the product of the multi-drug resistance gene MDR-1. The functional protein plays an important role in absorption, distribution, metabolism, and excretion of many drugs and substances used in veterinary medicine. P-glycoprotein is a pump found in tissues of the intestine, brain, biliary system, kidneys, placenta, and testes. Its normal role is to transport substrate drugs across cell membranes to be eliminated from the body. So, if a substance or drug is a substrate for P-glycoprotein, it is transported from inside the cell to outside the cell. When normal, P-glycoprotein may be considered “protective” in that it pumps potentially toxic things out of tissues so they may be eliminated from the body.
Altered function of P-glycoprotein is the result of a mutation in MDR-1 (more recently named ABCB1). Altered function of the gene product, P-glycoprotein, makes affected dogs susceptible to side effects when given certain medications that are substrates of P-glycoprotein. In other words, affected dogs are not able to pump certain medications out of cells to be eliminated, and they may have serious adverse drug reactions.
Impact on Medications
Problematic medications may include ivermectin or milbemycin used to treat certain parasites, loperamide used to treat diarrhea, and chemotherapy agents such as vincristine, vinblastine, and doxorubicin used to treat cancer. Others include acepromazine, butorphanol, and erythromycin. Selamectin and moxidectin, when used at much higher dosages than recommended for heartworm prevention, may cause serious side effects in affected dogs. The dose of ivermectin, selamectin, milbemycin and moxidectin in commercial canine heartworm preventatives are low enough to be used safely in dogs with the mutation when used according to the manufacturer’s label instructions. When these drugs are used at higher dosages or frequencies to treat other conditions (i.e. sarcoptic or demodectic mange), dogs with the mutation may develop serious life-threatening neurotoxicity.
Signs of neurotoxicity include ataxia (instability when walking), tremors, restlessness, hypersalivation, elevated respiratory rate, loss of vision, vomiting, stupor or confusion. If your dog experiences any of these signs whilst on a medication, they should be immediately be evaluated by a veterinarian. The neurotoxicity may result in coma and death.
Many drugs use P-glycoprotein, and some are still safely used in dogs with the mutation. Drugs that are known to be pumped out of the brain by P-glycoprotein include cyclosporine, digoxin and doxycycline. These appear to be tolerated by dogs with the MDR-1 mutation. Other drugs like morphine, buprenorphine and fentanyl may use the protein, and appear to be tolerated in dogs with the mutation. In humans, the following are reported to use P-glycoprotein, but there is no data in dogs as to whether they are or are not pumped by canine P-glycoprotein. Therefore, they should be used with caution: domperidone, etoposide, mitoxantrone, ondansetron, paclitaxel and rifampicin.
The mutation in MDR-1 has been identified in the Collie, Australian Shepherd, Long-Haired Whippet, Silken Windhound, McNab, Border Collie, English Shepherd, German Shepherd, Old English Sheepdog, and Shetland Sheepdog. 5% of mixed breed dogs (e.g. a St. Bernard mix) have also been found to have the mutation – especially if they mix is with a known at risk breed such as an Australian Shepherd. Note that ~ 70% of collies in the USA have the mutant gene and it is expected that the numbers worldwide are similar.
Testing for the Mutation
There is a valuable and cost-effective test to determine if your dog has this mutation. It is conducted at the Washington State University Veterinary Clinical Pharmacology Lab. To submit a sample, your veterinarian will collect and submit blood or cells collected from a cheek swab. The DNA from the sample is then evaluated by use of PCR (Polymerase Chain Reaction). The report indications if they are normal/normal, mutant/normal (heterozygote) or mutant/mutant (homozygote). Dogs may be tested once weaned from the mother. It is important that dogs are weaned, as cells from mother’s milk sticks to the mouth of the puppy and result in a false positive test. It is not always easy to determine if a dog is mixed with an at-risk breed. We recommend testing mixed breed dogs when considering treatment with medications that use P-glycoprotein. We recommend any at risk breed before such treatments as well.
Dogs that do not possess the mutation may be used for breeding, but dogs that possess the mutation should not be used for breeding, as they can pass the mutation to offspring. Dogs of the known affected breeds should be tested prior to breeding. It has been argued that, because the mutation is found in such a large number of collies and Australian Shepherds, it may be necessary to use normal/mutant dogs in breeding programs to maintain a large enough pool of good breeding stock. Guidelines for breeders to follow in this situation are available from the Washington State University Veterinary Diagnostic Lab. The intention of these guidelines is to produce future generations of dogs with a decrease in the frequency of the MDR-1 mutation.