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.
.Forum
Adverse Drug Reactions in Herding Breeds of Dogs and Cats
By Dr. Susan Muller Esneault
Filed Under: Dogs, Cats, General Care


Do you own a collie or an Australian shepherd?  Have you been cautioned that they may be particularly sensitive to certain drugs, or have you heard not to
give them certain medications?  Parasiticidal drugs, especially the avermectin group of dewormers:  ivermectin (Heartguard®), selamectin (Revolution®),
milbemycin (Interceptor®), and moxidectin (ProHeart®) may result in toxicity of the central nervous system when given above therapeutic levels.  Do you ever
wonder why these potentially lethal reactions occur when most other breeds have a wide safety margin when using these drugs?  Most idiosyncratic drug
reactions in veterinary patients are seen in herding breeds of dogs or in cats, which have a narrower therapeutic dose range for these drugs.  These same
breeds of dogs can be sensitive to various treatments such as chemotherapy as well.

It has recently been determined that some herding breeds of dogs have a single mutation in a gene coding for a particular protein (P-glycoprotein) that will
drastically affect the absorption, distribution, metabolism, and excretion of a variety of medications used in veterinary medicine.  In herding breeds of dogs
there is a defined mutation called MDR1-1∆ (multidrug resistance gene), also called ABCB1, which affects P-glycoprotein function.

P-glycoprotein is a rather larger protein that functions as a pump to transport drugs across cell membranes.  This pump requires energy in the form of ATP
allowing it to function against steep concentration gradients.  When a drug is transported by P-glycoprotein it is actively transported from intracellular (within
the cell) to extracellular space (outside the cell).  It is speculated that this protein serves an important function in protecting living beings, from one-celled
organisms to the most complex animal systems, by minimizing that particular being’s exposure to potentially toxic substances.  The protein functions by
pumping toxins out of protected sites and promoting their excretion and elimination.

The primary absorptive site for orally administered drugs is the villus tip of enterocytes (intestinal cells) located with the gastrointestinal (GI) tract.  P-
glycoprotein is present on the luminal border of these intestinal epithelial cells where it transports drugs from the cytoplasm back into the intestinal lumen
where they can be eliminated.  In this way, P-glycoportein plays an additional role in drug elimination by limiting intestinal absorption and promoting fecal
excretion of potentially toxic substances.

There are many barriers throughout the body protecting what is termed “privileged tissue”.  These barriers include the blood-brain, blood-placenta barrier,
and the blood-testes barrier.  The term “privileged” means that very few substances are allowed across this barrier.  P-glycoprotein has an important function
in this barrier by minimizing the distribution of a substance to these tissues.  In dogs totally lacking this protein they are considered to be homozygous for the
defect (in their genetic make-up they have 2 genes for the MDRI-l∆ mutation) and ivermectin a common dewormer and heartworm preventative, in even low
doses will induce neurologic toxicosis.  This is true for many other drugs as well, even including many chemotherapy agents like doxorubicin and vincristine,
and cardiac drugs such as digoxin and corticosteroids.

P-glycoprotein itself does not have any metabolic functions but it does work in conjunction with the CYP3A enzyme.  The CYP3A enzyme is one of the most
abundant cytochrome enzymes and is responsible for the metabolism of approximately 60% of all known drugs.

Complicated relationships may occur between P-glycoprotein, CYP3A, substrates, and even other substances called inhibitors.  A drug inhibitor is a drug that
interferes with the P-glycoprotein/CYP3A substrate system.  Drugs such as Erythromycin, Ketoconazole, Cyclosporine and Tracrolimus are all drug
inhibitors.  Using any one of these inhibitor drugs concurrently with another drug eliminated by P-glycoprotein substrates such as Vincristine or Digoxin may
result in drug toxicosis regardless of whether the MDR1-1∆ mutation is present or
not..                                                                                                                     

Breeds in which the MDR1-1∆ mutation has documented occurrences include:  Longhaired whippet, Silken windhound, Collie, Australian shepherd, English
shepherd, the McNab collie, Old English sheepdog, Shetland sheepdog, and the German shepherd.  White-coated dogs such as the white German shepherd
have a greater frequency of the MDR1-1∆ mutation than do other colors.

A study published in the American Journal of Veterinary Research during 2002 found that 75% of the collies from the Northwestern United States had at least
one mutant gene (heterozygous) for the MDR1-1∆ mutation, while 35% of those had two mutant genes and are termed homozygous for the defective gene.  
In Australian sheepdogs, 16.6 % of the population carries the defective gene, while Shetland sheepdogs are affected at an 8.4% level and Old English
sheepdogs at a lesser 3.6% level.  Other herding dogs such as the bearded collie and Australian cattle dog have not been shown to harbor the defective
gene, presumably as a result of their varied ancestry.

It is important to test for the MDR1-1∆ mutation for it allows veterinarians to determine whether it is safe to administer drugs that are eliminated by the P-
glycoprotein.  A simple cheek swab sample may be submitted for DNA analysis to determine the existence of the MDR1-1∆ mutation in any particular pet.
These samples should be forwarded to:

          Veterinary Clinical Pharmacology Laboratory (VCPL)
          College of Veterinary Medicine
          Washington State University
          509/335-3745

In pets reacting to acute exposure to avermectins or other drugs and treatments eliminated by P-glycoprotein, the clinical signs will become severe within a
few hours of exposure.  Most of the clinical signs relate to depression of the Central Nervous System (CNS) and include ataxia, weakness, and recumbency
(the pet is unable to get up), and in severe cases a coma may develop.  The pet may also appear to be blind and  muscle tremors may sometimes occur.  
Additional clinical signs include mydriasis (dilated pupils), hypothermia (low body temperature), shallow breathing, vomiting or salivation. Clinical signs may
persist for days or weeks, dependent upon the type of drug resulting in the toxicity.

Temporary relief is sometimes achieved with physostigmine, neostigmine or treatment with picrotoxin.  Additional treatment is supportive and may require:  
fluid therapy, respiratory support, maintenance of body temperature, and/or the use of a feeding tube.  Length of treatment depends upon the half-life of the
drug causing the toxicity.  The half-life of a drug refers to the length of time it takes to eliminate 1⁄2 of the drug in one individual’s system.  With ivermectin the
toxicity typically lasts 2 days, while it may take up to 11 days to eliminate selamectin or up to 19 days for moxidectin.