Multi Drug Resistance
explanation is that MDR1 is what is causing Collie and Sheltie
to die when treated with Ivomec. That much is known by most dog
is only a small part of the truth.
dog breeds are more sensitive to certain drugs compared to other
For example, Australian Shepherds, Collies, Longhaired Whippets
and other breeds are more sensitive to antiparasitic and anticancer
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.
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.
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.
the research report from UC Davies, California
that have been documented to cause problems in dogs with the MDR1
(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
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.
(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
(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).
(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).
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.
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
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);
- Vinblastine (anticancer drug);
- Vincristine (anticancer drug).
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:
A list of dangerous
drugs from Canada
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.
in a MDR1 affected dog who has been exposed to any of these drugs
with multidrug sensitivity typically display neurological symptoms
after drug admission such as hypersalivation, ataxia, blindness,
tremor, depression, coma, respiratory compromose, and death.
of your MDR1 results
is how you interpret the results of your dog
recessive mode of inheritance.
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.
Windhound community seem to be the only one of the affected breeds,
to make a serious effort to breed it out.
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
Shephard (recently discovered)
I have seen
Skye Terrier mentioned as well, but not on any researchers page
so that may just a rumour.
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
background of studies of MDR1
Working Collie Association
is not just about ivermectin in Collies
about avermectins and milbemycines
Interview with Mark Neff,one of the MDR1 researchers