Multidrug Sensitivity MDR1

 

MULTIDRUG SENSITIVITY - MDR1

Why are some breeds more sensitive to the effects of drugs than other breeds? Which drugs have been reported to cause problems? At Washington State University's College of Veterinary Medicine you can get your dog tested for drug sensitivity and keep up with the latest research.

 

It is well known that Collies and related breeds can have adverse reactions to drugs such as ivermectin, loperamide (Imodium®), and others. It was previously unknown why some individual dogs were sensitive and others were not. Advances in molecular biology at the Veterinary Clinical Pharmacology Laboratory at Washington State University's College of Veterinary Medicine have led to the discovery of the cause of multi-drug sensitivity in affected dogs. The problem is due to a mutation in the multi-drug resistance gene (MDR1). This gene encodes a protein, P-glycoprotein, that is responsible for pumping many drugs and other toxins out of the brain. Dogs with the mutant gene can not pump some drugs out of the brain as a normal dog would, which may result in abnormal neurologic signs. The result may be an illness requiring an extended hospital stay--or even death.

 

A test has recently been developed at Washington State University to screen for the presence of the mutant gene. Instead of avoiding drugs such as ivermectin in known susceptible breeds, veterinarians can now determine if a dog is normal, in which case the drug can be administered or abnormal, in which case an alternative treatment can be given.

 

Owners and breeders can submit samples for testing. All that is needed for the test is a cheek brush sample that can be obtained by the owner and sent by mail for analysis.

Affected Breeds

 

Approximately 3 of every 4 Collies in the United States have the mutant MDR1 gene. The frequency is about the same in France and Australia, so it is likely that most Collies worldwide have the mutation. The MDR1 mutation has also been found in Shetland Sheepdogs (Shelties). Australian Shepherds, Old English Sheepdogs, German Shepherds, Long-haired Whippets, Silken Windhounds, and a variety of mixed breed dogs.

The only way to know if an individual dog has the mutant MDR1 gene is to have the dog tested. As more dogs are tested, more breeds will probably be added to the list of affected breeds.

 

To test your dog contact : the Washington State University Veterinary Clinical Pharmacology Laboratory (WSU VCPL) to request a test kit.

Send an email to VCPL@vetmed.wsu.edu or contact your own veterinaryclinic

 

Problem Drugs

 

Many different drugs and drug classes have been reported to cause problems in Collies and other herding breed dogs that carry the MDR1 mutation.We and other researchers have documented the toxicity that occurs with several of these drugs.

 

 

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.