Dogs with the MDR1 Mutation: Drug Sensitivities

MDR1 mutation affects more than just Collies – and involves more drugs than ivermectin.

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[Updated January 9, 2019]

Most dog owners are aware that Collies and other herding breeds may be sensitive to ivermectin, used for heartworm prevention and to treat certain parasites. But did you know that these dogs can also be sensitive to a number of other drugs, and that other breeds can also be affected?

mdr1 collie

It’s been known since 1983 that ivermectin can cause neurologic toxicity in some, but not all, Collies. In affected dogs, toxicity is caused by doses of ivermectin that are 1/200th of the dose needed to cause toxicity in normal dogs. Symptoms of neurologic toxicity can include uncoordination or loss of balance (ataxia), depression, disorientation, excess salivation, pupil dilation, nystagmus (abnormal movement of the eyes), blindness, tremors, recumbency (inability to get up), coma, respiratory compromise, and even death.

But the next big accomplishment in gaining an understanding of exactly what was responsible for the toxic effects of ivermectin in some dogs came in 2001, when Katrina Mealey, DVM, PhD, DACVIM, DACVCP, at Washington State University College of Veterinary Medicine, identified a mutation in the MDR1 gene that causes ivermectin sensitivity. The discovery led to WSU’s development of a test that can detect the mutant gene, so that dogs who are susceptible to this toxicity can be identified.

The MDR1 Mutation Test

Dogs can have either two copies of the defective gene (homozygous, double recessive), or one defective gene and one normal gene (heterozygous). Dogs with two copies will be most severely affected. Dogs with one copy are less sensitive (able to tolerate a higher dose before adverse effects are seen), but they are more sensitive than normal dogs.

Further research revealed that dogs with the MDR1 mutation are sensitive to a number of different drugs, not just ivermectin. Melissa Best, DVM, who went to veterinary school at WSU, explains, “MDR stands for ‘multidrug resistance.’ The protein encoded by this gene is P-glycoprotein (PGP) and is an important protein for keeping potential neurotoxins from entering the brain. The MDR1 mutation means that this protein is improperly coded and cannot do its job.”

The MDR1 mutation allows drugs to build to toxic levels in the brain, and is now referred to as “multidrug sensitivity.” Toxicity may occur from a single high dose or frequent low doses of problem drugs. Topical application of certain drugs can also cause toxicity, and the effects may last longer, but it generally takes higher doses.

The discoverer of the mutation of the MDR1 gene and establishment of testing procedures, WSU is the sole patent holder for the test to detect the mutant gene. The test requires only a simple, non-invasive cheek swab that you can collect yourself and send to WSU’s Veterinary Clinical Pharmacology Laboratory (VCPL). The test costs $70, with a discount for more than four dogs. It can be performed on any dog, including mixed breeds, at any age after weaning. The test will identify whether a dog has one or two copies of the defective gene. It takes about two weeks to get results.

Heartworm Preventives and the MDR1 Mutation

All heartworm preventive medications can affect dogs with the MDR1 mutation, including ivermectin (Heartgard), milbemycin (Interceptor, Sentinel), selamectin (Revolution), and moxidectin (ProHeart, Advantage Multi). The very low doses used for heartworm prevention, however, should not cause any harm, even to dogs with two copies of the defective gene.

silken windhound

“I don’t know of any homeopathic or naturopathic alternatives to these drugs, particularly for heartworm,” says Dr. Best. “While I am very pro-holistic care, the risk of death from heartworms is greater than the risk of the drugs (especially at the low doses used for prevention). I recommend using commercial heartworm preventatives under the direction of a veterinarian.”

The higher doses of these medications that are used to treat demodectic mange, sarcoptic mange, ear mites, and other parasites, however, should be avoided in all affected dogs. Generic ivermectin preparations such as Ivomec 1% solution should not be given to affected dogs, as the potential for toxicity from the wrong dosage is too great (the instructions on many websites result in dosages at least 10 times too high). Long-acting injectable products such as ProHeart 6 may also be problematic for affected dogs.

Toxicity can also occur from eating the manure of other animals, such as horses or sheep, after they are treated for parasites with products containing ivermectin. Pesticides with ivermectin used to treat a home or yard may cause toxicity if an affected dog is exposed to the area afterward.

Ivermectin has the most potential for toxicity. Dogs with normal MDR1 genes can usually tolerate oral dosages as high as 2,500 mcg/kg of body weight before signs of toxicity are seen, while dogs with two copies of the defective MDR1 gene can tolerate only up to 100 mcg/kg of oral ivermectin. No toxicity was seen when affected dogs were given 28 to 35.5 mcg/kg monthly for one year. (For comparison, Heartgard contains 6 to 12 mcg/kg.)

Toxicity has been seen in affected dogs receiving oral doses that were 30 times the heartworm preventive dose of moxidectin and 10 times the regular dose of milbemycin. Selamectin caused toxicity at 2.5 times the recommended dose when that amount was given orally, but higher doses are tolerated when the product is applied topically, as directed.
Other avermectins can also cause toxicity, including doramectin (Dectomax), eprinomectin (Eprinex), and abamectin.

Spinosad, a flea-control medication included in Comfortis, Trifexis, and other products, increases the risk of neurological toxicity even in normal dogs when combined with high doses of ivermectin (and possibly other drugs) used to treat parasites. While theoretically safe, use caution when combining Heartgard or other ivermectin heartworm preventive drugs with products containing spinosad for affected dogs. Do not combine high doses of ivermectin with spinosad for any dog.

Other Drugs and MDR1

Some additional drugs are known to cause problems for dogs with the MDR1 mutation, while others are suspected to be problematic. A few drugs affected by PGP appear to be safe to use in normal doses. “There are many known drugs which are pumped out of the brain by p-glycoprotein,” says Dr. Best. “However, not all seem to cause toxicity in mutant dogs. Clearly more research is needed to understand the mechanisms at work.”

Drugs that are known to affect or may affect dogs with the MDR1 mutation include some used to treat cancer, pain, parasites, bacterial infections, diarrhea, vomiting, and anxiety, as well as pre-anesthetic drugs. In addition to ivermectin, the most commonly used problem drugs are acepromazine (Ace), butorphanol (Torbutrol, Torbugesic), and loperamide (Imodium). Most of these drugs require a prescription, but loperamide, an anti-diarrheal medication, is available in over-the-counter preparations.

MDR1 Breeding Considerations

Ideally, only dogs with no copies of the MDR1 mutation would be used for breeding. This may not be feasible or even optimal in some cases, however, particularly in heavily affected breeds, where the rest of the gene pool would be too limited, which leads to other problems. Any dog with the mutation may pass it along to their offspring, but dogs with just one copy of the mutation can also produce normal puppies, particularly when bred to dogs that do not carry the mutation at all. In this way, the population of affected dogs can be reduced through subsequent generations.

What To Do

Even if you don’t plan to breed, all dogs from affected breeds should be tested for the MDR1 gene for their own protection. Mixed-breed dogs from affected breeds or whose parentage is unknown should also be tested, as it’s impossible to tell for sure just by looking at a dog what its ancestry might be.

Before the genetic test became available, vets often repeated the adage, “White feet, don’t treat!” as a reminder that such dogs might be at risk, since many herding breeds and mixes have white feet. This is not reliable, however, as some dogs with white feet may have normal genes, and dogs with non-white feet may be affected by the mutation. Dr. Mealy recommends testing all mixed-breed dogs with unknown breed status, as one exposure to a drug to which they are sensitive could be fatal.

“The biggest problem I have seen with MDR1 mutants is accidental exposure by owners who were unaware of the problem,” says Dr. Best. “I have seen several dogs die from this problem after being exposed to ivermectin products.

“The worse case that I saw where the dog survived was an Australian Shepherd from Montana who became exposed after licking up a dollop of dewormer that had dropped out of a horse’s mouth when the owner was deworming it. The dog was flown on a private jet to WSU, with a private vet tech hired to breathe for the dog, as he was severely affected by the time he had been brought to his veterinarian (within hours of exposure to the drug).

“That patient was on a ventilator for nearly two weeks and eventually made a full recovery, however the bill was well over $10,000 and not everyone can fly a dog to a referral center on a private jet! I have also seen dogs become affected who ate horse manure after the horses had been dewormed with Ivermectin.”

If tests show that your dog is affected by the MDR1 mutation, or if your dog could be affected and has not been tested, make sure that your vet is aware of potential drug sensitivity. You may want to give your vet a copy of the list of drugs from the VCPL website to include in your dog’s file. Be sure to remind your vet of the situation any time that your dog needs to be anesthetized or sedated so that the wrong medications will not be given.

If you use any drug that might cause toxicity, start with low doses and gradually increase the amount that is given over a few days as long as no adverse side effects are seen. Continue to monitor your dog closely for signs of toxicity, particularly when the drug is given daily, as chronic toxicity caused by cumulative effects could develop.

If your dog shows signs of toxicity after applying a topical product, immediately bathe your dog with soap to remove as much of the product from the skin as possible.

If your dog ingests a topical product or if you see signs of toxicity after giving oral medication, contact your vet immediately. If ingestion was recent, your vet may induce vomiting and give activated charcoal. Further supportive care, including IV fluids and ventilation, may be needed if signs are severe. Dogs may recover if supportive care can be offered for long enough, but it can take days or weeks before enough of the drug breaks down on its own. “Sadly,” says Dr. Best, “Because we have no way to get the neurotoxic drugs out once they are in the brain, most dogs are not able to be saved once we recognize a toxicity problem.”

Mary Straus is the owner of DogAware.com. She and her Norwich Terrier, Ella, live in the San Francisco Bay Area.

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Mary Straus has been a regular contributor to Whole Dog Journal since 2006. Mary first became interested in dog training and behavior in the 1980s. In 1997, Mary attended a seminar on wolf behavior at Wolf Park in Indiana. There, she was introduced to clicker training for the first time, and began to consider the question of how we feed our dogs after watching the wolves eat whole deer carcasses. Mary maintains and operates her own site, DogAware.com, which offers information and research on canine nutrition and health. DogAware.com has been created to help make people more "aware" of how to make the best decisions for their dogs. It's designed for people who like to ask questions and understand the reasoning behind decisions, rather than just being told what to do.  Mary has spent years doing research for people whose dogs have health problems, or who just want to learn how to feed them a better diet. Over this time, she has learned a great deal about dog nutrition and health, including the role of diet, supplements and nutraceuticals.  In 2007, she was asked by The Ivy Group to contribute to The Healthy Dog Cookbook. She previously also wrote a column for Dog World.

8 COMMENTS

  1. Mary – I have a two year old mini Australian Shepherd (Ezekiel) which I got tested as a pup and his results state Mutant/Normal. He has been neutered and will not be passing onto other dogs. My question, after reading your article, is that can I put him on heart worm meds. He brother (Rufus) , a rescue – same breed – is a survivor of a mild case (thank God) of heart worms.
    He takes monthly Interceptor Plus for 24.1-50 lbs. I was told I can give this to my Mutant dog, Ezekiel. One vet said yes, but honestly I am still worried. Any advice would be greatly appreciated!
    Thank you – Veronique Dunagin, Los Lunas, New Mexico

    • Veronique, I wouldn’t hesitate to give your dog with a single copy of the MDR1 mutation heartworm prevention medication at normal doses. I would not give him high doses sometimes used to treat mange, or double up on heartworm meds, as is sometimes done in areas where heartworm resistance has been seen (primarily around the Mississippi Delta). I would also not use flea/tick meds that contain spinosad, such as Comfortis or Trifexis, as this can increase the neurological effects. Heartworm prevention meds such as Heartgard (ivermectin) and Interceptor (milbemycin) should be safe at heartworm-prevention doses, even for dogs with two copies of the mutation.

  2. Mary,
    Has any of your research and data collection included data on Comfort Retrievers, ie crosses of Golden Retrievers and Cocker Spaniels (1/2 English and 1/2 American)? We adopted two blue merle puppies and were unaware of the drug sensitivities until warned by my vet tech. I was aware that breeding two merles together usually had a bad outcome but was not totally sure what that bad outcome was.
    I am leaning toward using Symparica Trio for fleas, ticks, heartworm, and internal parasites. Comments?
    Thanks, Patti

  3. My dog tested for this. And out of nowhere he has became aggressive. Is that normal? None of my local vets know anything about this.

    • Deidra, I know of no link between aggression and the MDR1 mutation, unless possibly if you gave a prohibited medication that caused neurological damage, but I’ve never heard of such a thing. Aggression can be linked to hypothyroidism, but that’s not linked to the mutation, either. Best to see a behaviorist who uses positive methods (using punishment for aggression is very dangerous, as it can make the aggression worse).
      http://dogaware.com/articles/wdjhypothyroid.html

  4. When i started with my two girls five years ago I had no clue about testing until the vet put them on some multi heart and tic, something new. One of my girls Rosie started to have a seizure fit on the floor. I stop the meds and called the vet, not much help. Now I am at a loss, we had her tested and she does have the MDR1 on both sides her sister is clear winch I found strange but it is possible. She needs some kind of protection. I had her on Heartguard for 4 years she was fine. Now I am looking for organic ways to keep her healthy Help pleases.

    • Kimberly, if your dog did fine with Heartgard, I would return to that. It’s possible that the reaction you saw was linked to some of the newer drugs (isoxazoline class) that can lower the seizure threshold in dogs already prone to seizures, rather than to the MDR1 mutation. Heartgard should be safe for either. There are not “organic” ways to prevent heartworm infections. More info:
      http://dogaware.com/articles/newsfleatick.html

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