MDR1?

Many different drugs and drug classes have been reported to cause problems in Collies and other herding breed dogs that carry the MDR1 mutation. WA State School of Veterinary Pharmacology has documented the toxicity that occurs with several of these drugs.

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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 andongoing 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.

Drugs that are known to be pumped out of the brain by the protein that the MDR1 gene is responsible for producing but appear to be safely tolerated by dogs with the MDR1 mutation:

• Cyclosporin (immunosuppressive agent)-While we know that cyclosporin is pumped by P-glycoprotein (the protein encoded by the MDR1 gene), we have not documented any increased sensitivity to this drug in dogs with the MDR1 mutation compared to “normal” dogs.  Therefore, we do not recommend altering the dose of cyclosporin for dogs with the MDR1 mutation, but we do recommend therapeutic drug monitoring.
• Digoxin (cardiac drug)- While we know that digoxin is pumped by P-glycoprotein (the protein encoded by the MDR1 gene), we have not documented any increased sensitivity to this drug in dogs with the MDR1 mutation compared to “normal” dogs.Therefore, we do not recommend altering the dose of digoxin for dogs with the MDR1 mutation, but do recommend therapeutic drug monitoring.
• Doxycycline (antibacterial drug)- While we know that doxycycline is pumped by P-glycoprotein (the protein encoded by the MDR1 gene), we have not documented any increased sensitivity to this drug in dogs with the MDR1 mutation compared to “normal” dogs. Therefore, we do not recommend altering the dose of doxycycline for dogs with the MDR1 mutation.

Drugs that may be pumped out by the protein that the MDR1 is responsible for producing, but appear to be safely tolerated by dogs with the MDR1 mutation:

• Morphine, buprenorphine, fentanyl (opioid analgesics or pain medications)-We suspect that these drugs are pumped by P-glycoprotein (the protein encoded by the MDR1 gene) in dogs because they have been reported to be pumped by P-glycoprotein in people, but we are not aware of any reports of toxicity caused by these drugs in dogs with the MDR1 mutation.We do not have specific dose recommendations for these drugs for dogs with the MDR1 mutation.

The following drugs have been reported to be pumped by P-glycoprotein (the protein encoded by the MDR1) in humans, but there is currently no data stating whether they are or are not pumped by canine P-glycoprotein.Therefore we suggest using caution when administering these drugs to dogs with the MDR1 mutation.

• Domperidone
• Etoposide
• Mitoxantrone
• Ondansetron
• Paclitaxel
• Rifampicin

There are many other drugs that have been shown to be pumped by human P-glycoprotein (the protein encoded by the MDR1 gene), but data is not yet available with regard to their effect in dogs with the MDR1 mutation. 

Can Collie crosses or other herding breed crosses carry the mutant MDR1 gene and have an adverse reaction to a normal dose of drugs?

Yes, it is less likely in a mixed breed, but still possible. We have found the mutant gene in a Saint Bernard mix that had an adverse drug reaction. The veterinarian did note that each eye was a different color, like some Australian Shepherds.

How old must a dog be before it can be tested? 
 
A puppy can be tested as soon as it is weaned from its mother.  Why do we recommend waiting until the puppy is weaned? Since we sample the inside of the dog’s mouth, and milk can contain a few cells from the mother, it is possible that the puppy’s sample could contain enough of the dam’s DNA to generate a false result.
 
Can mixed breed dogs have the MDR mutation? 
 
YES!  We have found the MDR1 mutation in many mixed breed dogs—even dogs that don’t look like herding breed dogs.  Mixed breed dogs should be tested for the mutation before receiving anti-mange doses of ivermectin. 
 
Why are affected dogs called “mutants”? 
 
A gene is a section of DNA that is responsible for producing a particular protein in the body.  When a dog (or other organism) has a DNA sequence that produces a defective protein, that animal is said to have a mutation in that gene.  Individual animals that have a mutation in a particular gene are considered to have the mutant form of the gene.  Unfortunately, the word “mutant’ in lay language has been associated with a negative connotation. 
 
What heartworm prevention products can I use if my dog has the MDR1 mutation? 
 
Fortunately, the dose of ivermectin, selamectin, milbemycin and moxidectin in the commercial heartworm preparations are low enough to be used safely even in dogs with the MDR1 mutation.  It is only when the drugs are used at high doses, such as those used to treat mange (50 times higher dose than the heartworm prevention dose), that dogs with the mutation will develop neurological toxicity.  Attempting to use large animal formulations of these drugs is likely to cause neurological toxicity because it is difficult to accurately measure