******MDR1 Collie Drug Sensitivity
MDR1 Breeding Guidelines
This chart provides guidelines for consideration when owners are contemplating
breeding dogs that may be affected by the MDR1 mutation. While it is ideal to use only "Normal/Normal"
breeding pairs, one must always consider other genetic factors in addition to the MDR1 gene. Because the MDR1 gene is
present in such a large percentage of Collies and Australian Shepherds, it may be necessary to breed "Normal/Mutant"
dogs in order to maintain a large enough pool of good breeding stock. By using thoughtful breeding strategies
including these guidelines, future generations of dogs will have a substantial decrease in the frequency of the mutant MDR1
gene.
MDR1 Breeding Pair Combinations and Outcomes
| Normal/Normal
Male | Normal/Mutant* Male | Mutant/Mutant
Male |
Normal/Normal Female | 100% Normal/Normal puppies
| Normal/Normal and/or Normal/Mutant puppies | 100% Normal/Mutant puppies |
Normal/Mutant*
Female | Normal/Normal and/or Normal/Mutant puppies | Any combination of puppies | Normal/Mutant and/or Mutant/Mutant
puppies |
Mutant/Mutant Female | 100% Normal/Mutant puppies | Normal/Mutant
and/or Mutant/Mutant puppies | 100% Mutant/Mutant puppies |
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:
- 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).
- Erythromycin.
Erythromycin may cause neurological signs in dogs with the MDR1 mutation. A mutant/mutant collie exhibited signs of
neurological toxicity after receiving erythromycin. After withdrawal of the drug, the dogs neurological signs resolved.
There were no other potential causes of neurological toxicity identified in the dog.
- 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).
- 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.
- 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.
- 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.
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.