Clinical perspective: the MDR1 mutation

I work as an on-duty veterinarian providing emergency care for pets. My patients are often seriously ill and require intensive medical care; decisions have to be made rapidly. For many of my patients, adverse reactions in response to drugs could potentially be severe. As a veterinarian, I would prefer that at least each of my Collie, Australian Shepherd and Shetland Sheepdog patients would be tested for MDR1 mutation before starting treatment. In this article I will tell you why.

The MDR1 gene produces a protein that plays significant role in drug transport inside the dog’s body. In dogs homozygous for the mutated form of MDR1 (having inherited the gene defect from both parents), this transport mechanism doesn’t work correctly. This predisposes the dog to many possibly severe side effects of many commonly used drugs.

The MDR1 mutation is very common in certain breeds. However, the same mutation could potentially be found in any breed.

BREED HETEROZYGOUS HOMOZYGOUS
Collie 42 % 36 %
Australian Shepherd 37 % 7 %
Shetland Sheepdog 19 % 8 %
Chinook 13 % 1 %
Old English Sheepdog 13 %  

Other breeds in which the mutation is common: Mini Australian Shepherds, Longhaired Whippets, Silken Windhounds and German Shepherd Dogs

The most well-known and very severe problem associated with MDR1 mutation is the susceptibility to toxic effects of antiparasitic drugs containing Ivermectin. Normally this drug doesn’t pass the blood-brain barrier, but in dogs homozygous for the mutation, this drug is able to enter the brain and cause even fatal paralysis and seizures. For example, the dosage of Ivermectin that is used to treat mange is toxic for these dogs. Ivermectin poisoning could also potentially happen if the dog eats large amounts of excrement of, for example, horses or sheep that have recently been treated with Ivermectin. Testing for the mutation is therefore advisable for the safety of farm dogs. 

The above-mentioned is far from being the only effect of the MDR1 mutation. The mutation alters the transport of many important drug groups. The transport protein encoded by this gene is needed in many organs. It is needed for proper drug removal out of the body as well as for reducing excessive absorption of drugs from the intestines. When this mechanism doesn’t work correctly, drugs reach higher concentrations inside the body than usual and stay inside the body for a longer time.

Many important drug groups require the proper function of the MDR1 gene to be used safely. Loperamide, a commonly used opioid used for treating diarrhea, is neurotoxic in dogs having two copies of the mutation. Loperamide cannot be used for dogs homozygous for the mutation. In dogs heterozygous for the mutation (carries one mutated copy), the dose of the drug should be reduced. In addition to Ivermectin, also other antiparasitic drugs of the Avermectin group and the deworming drug Emodepside can cause neurotoxicity in dogs carrying two copies of the mutation.

The MDR1 status of the dog also affects planning of anaesthesia and cancer medication. The transporter coded by the MDR1 gene carries also important sedative agents and pain medicaments such as the opioid Butorphanol and the tranquilizer Acepromazine. In dogs carrying two copies of the mutation, these drugs can have a stronger effect than usual, and the doses of these drugs need to be adjusted accordingly. Also the dosage of certain cancer medications should be drastically lowered in dogs carrying one or two copies of the mutation. The dosage of cancer medicaments should not be lowered in normal dogs or the effect of the drug diminishes. 

Many of the effects of the MDR1 mutation remain still unknown. The transport protein is also an important part of the blood-placental barrier and blood-testis barrier. It transports a large number of other drugs in addition to those mentioned earlier. Actual effects of these drugs and the effect on the fetus remain unknown.

In conclusion, as a veterinarian, I would always want to know the dog’s MDR1 status because I want to provide my patients with both the safest and most effective medical care possible. And please remember: Always inform your veterinarian if your dog’s MDR1 status has been tested.