MDR1 Multi Drug Resistance

The easy explanation is that MDR1 is what is causing Collie and Sheltie to die when treated with Ivomec. That much is known by most dog fanciers.

But that is only a small part of the truth.

Some dog breeds are more sensitive to certain drugs compared to other breeds.
For example, Australian Shepherds, Collies, Longhaired Whippets and other breeds are more sensitive to antiparasitic and anticancer drugs.

The problem is due to a mutation in the multidrug resistance gene (MDR1). The product of MDR1 gene, P-glycoprotein, is an important component of the blood-brain barrier that is responsible for pumping many drugs out of the brain.

Dogs with mutant MDR1 gene cannot remove some drugs out of the brain as normal dogs would, which may result in abnormal neurological signs. The result may be an illness requiring an extended hospital stay or even death of the dog.

In addition to its expression in the blood-brain barrier, P-glycoprotein expression occurs also in the intestinal tract, liver, and kidney. In these organs, the absence of P-glycoprotein will alter the pharmacokinetic properties of drugs identified as P-glycoprotein substrates, resulting in enhance oral bioavailability and/or reducing drug elimination through the liver, kidney, and gut. In consequence, plasma concentrations will increase and adverse drug reactivity may occur.

Download the research report from UC Davies, California

Drugs that have been documented to cause problems in dogs with the MDR1 mutation include:

• Ivermectin (antiparasitic agent)-While the dose of ivermectin used to prevent heartworm infection is SAFE in dogs with the mutation (6 micrograms per kilogram), higher doses, such as those used for treating mange (300-600 micrograms per kilogram) will cause neurological toxicity in dogs that are homozygous for the MDR1 mutation (mutant/mutant) and can cause toxicity in dogs that are heterozygous for the mutation (mutant/normal).
• Selamectin, milbemycin, and moxidectin (antaparasitic agents)-Similar to ivermectin, these drugs are safe in dogs with the mutation if used for heartworm prevention at the manufacturer’s recommended dose. Higher doses (generally 10-20 times higher than the heartworm prevention dose) have been documented to cause neurological toxicity in dogs with the MDR1 mutation.
• Loperamide (ImodiumTM; antidiarrheal agent)-At doses used to treat diarrhea, this drug will cause neurological toxicity in dogs with the MDR1 mutation.This drug should be avoided in all dogs with the MDR1 mutation.
• Acepromazine (tranquilizer and pre-anesthetic agent)-In dogs with the MDR1 mutation, acepromazine tends to cause more profound and prolonged sedation.We recommend reducing the dose by 25% in dogs heterozygous for the MDR1 mutation (mutant/normal) and by 30-50% in dogs homozygous for the MDR1 mutation (mutant/mutant).
• Butorphanol (analgesic and pre-anesthetic agent)-Similar to acepromazine, butorphanol tends to cause more profound and prolonged sedation in dogs with the MDR1 mutation.We recommend reducing the dose by 25% in dogs heterozygous for the MDR1 mutation (mutant/normal) and by 30-50% in dogs homozygous for the MDR1 mutation (mutant/mutant).
• Vincristine, Vinblastine, Doxorubicin (chemotherapy agents)-Based on some published and ongoing research, it appears that dogs with the MDR1 mutation are more sensitive to these drugs with regard to their likelihood of having an adverse drug reaction. Bone marrow suppression (decreased blood cell counts, particulary neutrophils) and GI toxicity (anorexia, vomiting, diarrhea) are more likely to occur at normal doses in dogs with the MDR1 mutation. To reduce the likelihood of severe toxicity in these dogs (mutant/normal or mutant/mutant), we recommend reducing the dose by 25-30% and carefully monitoring these patients. 
• Read more at the State University of Washington That page also talks about products that appear to be safe, and drugs to keep an eye on, although no reports of problems with MDR1 dogs have been reported yet

Another list of drugs that have been documented, or are strongly suspected to cause problems in dogs with MDR1 mutation:

- Acepromazine (tranquilizer):
- Butorphanol (pain control);
- Cyclosporin (immunosuppression drug);
- Digoxin (heart drug);
- Doxorubicin (anticancer drug);
- Ivermectin (antiparasitic drug);
- Loperamide (Imodium®, antidiarrheal drug);
- Moxidectin;
- Vinblastine (anticancer drug);
- Vincristine (anticancer drug).

Biochemical studies have shown that mutant MDR1 gene has the potential to act on over 50 different drugs. The following drugs may potentially cause problems when given to dogs that have the mutation:

- Domperidone;
- Etoposide;
- Mitoxantrone;
- Morphine;
- Ondansetron;
- Paclitaxel;
- Quinidine;
- Rifampicin.

A list of dangerous drugs from Canada

The list of drugs will change over time, as the scientists learn more, always try to keep yourself uptodate with the latest information if you have a dog that is affected (double carrier) of MDR1.

Symptoms in a MDR1 affected dog who has been exposed to any of these drugs

Dogs affected with multidrug sensitivity typically display neurological symptoms after drug admission such as hypersalivation, ataxia, blindness, tremor, depression, coma, respiratory compromose, and death.

Explanation of your MDR1 results

Here is how you interpret the results of your dog

Inheritance of MDR1
Autosomal recessive mode of inheritance.

And this is why we test our dogs. Knowing the status of MDR1 in our breeding dogs, will enable us to breed away from MDR1 safely over time, without loosing too much genetic diversity in the process.

The Silken Windhound community seem to be the only one of the affected breeds, to make a serious effort to breed it out.

MDR1 exists in humans too
There is even MDR2 and MDR3 In humans MDR1 is a hindrance in some cancer treatments. Studies and tests are done right now to find inhibitors of MDR1expression.

The following breeds are known to have MDR1, more will likely be found in the future

• Collie
• Shetland Sheepdog
• Australian Shepherds
• Miniature Australian Shepherds
• Old English Sheepdogs
• English Shephard
• mcNabb
• White Shephard (recently discovered)
• Long-haired Whippets,
• Silken Windhounds

I have seen Skye Terrier mentioned as well, but not on any researchers page so that may just a rumour.

DNA studies, particularly mitocondrial DNA, revealed that all breeds mentioned above share a common ancestor, a bitch that in all likelyhood lived in England during the 1800's, before the closing of studbooks began.

MDR1 resources

The background of studies of MDR1

Test your dog

Washington State University

American Working Collie Association

MDR1 Information Plattform

It is not just about ivermectin in Collies

Information about avermectins and milbemycines

Interview with Mark Neff,one of the MDR1 researchers

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Page updated January 3, 2009