Prior to becoming a veterinarian, I did a Ph.D. in genetics (I may be the only author of maize genetics paper whose corresponding address happened to be a veterinary clinic). Because of this, I’m interested in the amazing pace of advancements in canine genetics and will share what we already know and things that are coming down the pike in this and future installments. It’s been known for some time that Collies and other herding and sight hound breeds are particularly sensitive to a number of different drugs. The most familiar drugs are ivermectin and moxidectin (important anti-parasite drugs) but other drugs including loperamide (the active ingredient of Imodium) and certain anti-cancer drugs can also be a problem. Ivermectin is an important treatment for certain types of worms and mites (in humans, ivermectin is the critical drug in fighting river blindness caused by the parasite Onchocerca volvulus). In animals it is used both as a heartworm prophylactic and as a dewormer and miticide. It is the only cost-effective treatment for generalized demodex in dogs.
It is troubling to have patient patient who is hypersensitive who needs ivermectin or one of the other problem drugs and not knowing whether they will tolerate it. Dr. Katrina Mealey, a veterinarian at Washington State University identified the genetic mutation leading to this sensitivity in 2001 and for several years her lab has offered a screening test for this mutation that owners and breeders can perform at home using just a cheek swab (or from a blood sample drawn at the clinic for the “unswabbable” dog). The MDR1 gene produces a protein which pumps drug across cell membranes. In dogs with the MDR1 mutation, the protein is cut short and is non-functional (a deletion mutation which produces a premature “stop” codon).
Interestingly this same protein may be involved in chemotherapy resistance in human cancers and some mutations have been found in people that can alter human drug effectiveness.. Now when I see a new patient from an at-risk breed, I encourage owners to test their dog so we know in advance whether there may be problem drugs in the future. Dr. Mealey’s lab offers a cheek swab test that owners can order and submit themselves. Owners then communicate the result to us to ensure that the patient’s genotype is recorded in their medical record so we can treat their dog safely should an illness occur.
If you are concerned that your dog may be at risk, Dr. Mealey’s group has preliminary data on frequency of the mutation by breed:
Breed Approximate Frequency MDR1 mutation
- Australian Shepherd 50%
- Australian Shepherd, Mini 50%
- Border Collie < 5%
- Collie 70 %
- English Shepherd 15 %
- German Shepherd 10 %
- Herding Breed Cross 10 %
- Long-haired Whippet 65 %
- McNab 30 %
- Mixed Breed 5 %
- Old English Sheepdog 5 %
- Shetland Sheepdog 15 %
- Silken Windhound 30 %
Problem drugs in dogs with MDR1 mutation:
- Acepromazine (tranquilizer and pre-anesthetic agent): Dogs with MDR1 gene defects can be very sensitive to this drug. Doses should be reduced by 25% in pets with one copy of the gene (heterozygous) and 30%-50% in pets with two copies of the gene (homozygous).
- Butorphanol (analgesic and pre-anesthetic agent): Similar to acepromazine with the same dosage reduction advice.
- Emodepside (Profender-an anti-parasite medication): Although approved only for cats in this country it has been used in dogs and can cause neurologic toxicity in those with a defective MDR1 gene .
- Erythromycin (antibiotic): This drug has been reported to cause neurologic toxicity in dogs with the mutation.
- Ivermectin, selamectin, milbemycin, moxidectin (antiparasitic agents): While the dose of milbemycin or ivermectin in heartworm preventatives is too low to be a problem for dogs with the MDR1 mutation, higher doses of any of these avermectins can cause severe neurologic toxicity.
- Loperamide (ImodiumTM; antidiarrheal agent): we don’t routinely use or recommend Imodium in our patients since it is inappropriate for most cases of canine diarrhea but owners occasionally use it. This drug can cause severe neurotoxicity in dogs with the MDR1 mutation and should not be used.
- Vincristine, Vinblastine, Doxorubicin (chemotherapy agents): current evidence suggests that MDR1 dogs receiving these drugs can have excessive bone marrow suppression and doses should be reduced. Vincristine is an important drug for us not just for cancer but also for severe immune-mediated thrombocytopenia (ITP) which causes dogs to have bleeding problems due to low platelet numbers.
This list of drugs is just beginning: there are drugs which we know are also pumped by this transporter but which appear to be safe (cyclosporine, digoxin, doxycycline, many of the opiods) and drugs which may use this transporter (based on data from people) but which we don’t know much about yet (domperidone, etoposide, mitoxantrone, ondansetron, paclitaxel, rifampicin). As more research is done we have more information on the best treatment for all of our patients. The MDR1 gene is just one example of the development of “personalized pharmacogenomics” which in people is helping your doctor determine which drug might be most effective and safe in treating everything from your headache to your breast cancer. I guess in our case we should call it “dognalized pharmacogenomics”.