What is the multidrug resistance mutation (MDR1)?
The word mutation refers to a change in an animal’s genetic code. The phrase “multidrug resistance mutation 1 (MDR1)” refers to a specific mutation that can occur at a gene known as MDR1, also known as the ABCB1 gene.
Many herding breeds (most commonly collies and Australian shepherds) have a mutation at the MDR1 gene that makes them more sensitive to the negative effects of certain medications. These drugs include several antiparasitic agents (when given at high doses), the antidiarrheal agent loperamide (Imodium®), some sedatives and opioids, and several anticancer drugs.
Dogs with MDR1 mutations show negative effects from these drugs at doses that are readily tolerated by dogs without the mutation.
How does the MDR1 mutation make animals more sensitive to medication?
The MDR1 gene is responsible for the production of a protein known as p-glycoprotein. This protein acts as a pump in cells, helping to clear chemicals and potential toxins from the cell. P-glycoprotein plays an especially significant role in the blood-brain barrier that helps keep drugs and chemicals in the bloodstream from entering the brain.
- Animals with two functional copies of the MDR1 gene have a normal p-glycoprotein system, which helps make them more resistant to the effects of medications.
- Animals with two mutated copies of the MDR1 gene have abnormal p-glycoprotein and a non-functional p-glycoprotein system, which makes them more sensitive to the effects of certain medications.
How do drug effects differ in animals with MDR1 mutation?
The most significant effects of the MDR1 drug mutation are seen at the blood-brain barrier. The term “blood-brain barrier” is used to describe a filtering mechanism that keeps certain blood-borne substances from entering the brain tissue. In dogs with the MDR1 mutation, defective p-glycoproteins allow higher levels of drugs to enter the brain, increasing the neurologic effects of some medications.
Ivermectin and related drugs (milbemycin, selamectin) are commonly used in the prevention and treatment of parasites. They are common components of most canine heartworm preventives. At low doses, such as those used in heartworm prevention, ivermectin is safe even for dogs with the MDR1 mutation. At high doses, however, such as those used in treating parasites such as demodectic mange, ivermectin can cause neurologic effects in dogs with the MDR1 mutation.
"In dogs with the MDR1 mutation, defective p-glycoproteins allow higher levels of drugs
to enter the brain, increasing the neurologic effects of some medications."
Loperamide (Imodium®) is another drug with potential neurologic effects in dogs with the MDR1 mutation. This drug does not affect the brain in most dogs, due to p-glycoprotein’s ability to pump the drug out of the brain. Dogs with the MDR1 mutation, however, can experience neurologic effects from loperamide.
Sedatives, such as those commonly given as components of a balanced anesthetic protocol (acepromazine, butorphanol), may also show stronger effects in dogs with an MDR1 mutation; there is a subtle difference in degree and duration of sedation. These dogs can still receive typical anesthetic drugs safely, but veterinarians may choose to use lower doses in dogs who are suspected or known to possess an MDR1 mutation.
Chemotherapy drugs may trigger more severe side effects in dogs with MDR1 mutation. These effects can include gastrointestinal toxicity and bone marrow suppression, even at low doses.
How does a dog develop an MDR1 mutation?
The MDR1 mutation involves a deletion of four base pairs in the dog’s genetic code. This deletion results in the protein that is coded by this gene, p-glycoprotein, being abnormally short.
Each dog inherits two copies of the MDR1 gene – one copy from each parent. If a dog inherits two defective genes (a defective copy from each parent), the lack of normal p-glycoprotein production will lead to signs of MDR1 mutation. Dogs who inherit only one abnormal MDR1 gene may also show mild effects, though they will be less severe than a dog with two abnormal copies of the gene.
What is the likelihood that my dog is affected by the MDR1 mutation?
The MDR1 mutation is most commonly seen in herding breeds. The effects of the mutation vary in severity, depending on whether the dog carries one or two copies of the mutation. Affected breeds include:
- Collies (70%)
- Australian shepherds (50%)
- Shelties (15%)
- Border collies (5%)
- English shepherds (15%)
- German shepherds (10%)
- Old English sheepdogs (5%)
- Mixed breed (5%)
- Silken windhound (30%),
- Long-haired whippet (50%)
How can I know if my dog has an MDR1 mutation?
There is a commercially available test that assesses blood samples (or a cheek swab) for the presence of the MDR1 mutation. Ask your veterinarian about this test if your dog is a herding breed or if you suspect an MDR1 mutation.
