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MDR1 Gene Mutations - Why Do They Matter?

What is MDR1?

MDR1 stands for multidrug resistance. A mutation in this gene (also known as the ABCB1 gene) makes animals more sensitive to the negative effects of certain medications, even at normal doses that would not have adverse effects on most animals. Many herding breeds, including Collies, Australian Shepherds, Shetland Sheep Dogs, Long-haired Whippets, and Silken Windhounds are affected by this mutation. All dogs affected by the MDR1 mutation are thought to have descended from a single dog in Great Britain. Mutations of the MDR1 gene have been found in both dogs and cats.

The MDR1 gene codes for a substance called p-glycoprotein. P-glycoprotein is a pump that sits on the cell wall and clears drugs and toxins from inside the cells. This protein is particularly important in the cells that form the "blood-brain barrier" where drugs are blocked from entering the brain from the bloodstream. 

Each dog inherits two copies of the MDR1 gene – one copy from each parent. Animals with two functional copies of the MDR1 gene are more resistant to the effects of common medications. Research has shown that animals with two functional copies of the MDR1 gene require higher levels of anti-seizure medications than animals with one or two mutated copies of the gene.

If a dog inherits a defective copy of the gene 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 receiving two abnormal copies of the gene. Mixed breed dogs may be more likely to have a single abnormal gene.

In animals with two mutated copies of the MDR1 gene the p-glycoprotein that is produced is abnormal which means drugs can reach higher levels within the cells making the animal more sensitive to certain drugs. In addition, these animals will have an abnormal feedback mechanism from the pituitary gland to the adrenal glands, causing lower cortisol levels. The effects become apparent under periods of high stress, such as illness or extreme physical activity. These dogs may respond poorly to increased energy demands and exhibit evidence of relative adrenal insufficiency (similar to Addison's disease). In some cases, physiologic doses of corticosteroids are indicated.

Which drugs may cause problems for MDR1-deficient pets?

Drugs that should be used at lower doses or not at all include:

  • Analgesic/sedative: Acepromazine, Butorphanol
  • Antibacterial: Erythromycin
  • Antiparasitic: Octadepsipeptide, Doramectin, Eprinomectin, Ivermectin, Milbemycin, Moxidectin, Selamectin, Emodepside (At extralabel doses only; label doses for heartworm prevention in dogs and cats are safe according to current research, but use with extreme caution)
  • Chemotherapeutic: Antibiotic/antineoplastic agents, Vinca alkaloids, Taxanes, Actinomycin D, Doxorubicin, Vinblastine, Vincristine, Vinorelbine, Docetaxel, Paclitaxel,
  • GI Antidiarrheal/Antiemetic: Loperamide, Ondansetron (Metronidazole has been incriminated, however it does not use the p-glycoprotein system in metabolism. Metronidazole can have neurologic side-effects but they are not related to the MDR1 gene.)
  • Apomorphine (used to induce vomiting)

Can animals with normal MDR1 genes be affected by these drugs?

Drug to drug interactions can also cause defective p-glycoprotein function. Even though no gene mutation is present, animals can show symptoms of p-glycoprotein dysfunction. Drugs to be avoided in MDR1 mutation animals should also be avoided or used at lower doses in animals receiving spinosad (Comfortis; Tri-Fexis), afoxolaner (NexGard), fluralaner (Bravecto), lotilaner (Credelio), sarolaner (Simparica), or related flea preventatives, or ketoconazole, itraconazole, fluconazole or related antifungals, then serious drug-drug interactions can occur. It is best to avoid these combinations altogether. Further, these flea preventives are contraindicated for dogs prone to seizure disorders.

What are the symptoms of MDR1 drug toxicity?

Symptoms of MDR1 drug toxicity often present as vague neurologic signs, such as weakness, lethargy, ataxia, and disorientation. The pet may be stumbling and bumping into things. In severe cases, the patient will become nonambulatory and even comatose, and ventilator-assisted respiration may be necessary.

What is the treatment for MDR1 drug toxicity?

The most important treatment is intensive supportive care, including IV fluids, nutritional support, and diligent patient monitoring. Recovery may be a lengthy process.

How do I know if my pet carries this mutation?

Testing to determine whether your pet has the MDR1 mutation can be performed by submitting a cheek swab to Washington State University Veterinary Clinical Pharmacology Laboratory

Is MDR1 mutation associated with other diseases?

Interestingly, MDR1 deficiency has been studied in cases of ulcerative colitis and Crohns Disease in humans. A link has been made between MDR1 deficiency and a variety of diseases including including cystic fibrosis, neurological diseases, retinal degeneration, anemia, cholesterol, and bile transport defects.
 

 

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