The MDR1 Mutation
The Multi Drug Resistance, or MDR1 gene, is the site of a noteworthy mutation found in most herding breeds as well as a few sighthounds. MDR1 makes the natural barriers in the body more permeable. This means, in most cases, that affected collies may react negatively to therapeutic drugs at far lower doses than their unaffected counterparts. The mutation is very common in collies: depending on the source, 55 to 70% of the collie population is affected by this mutation. As the mutation is dominant, one affected parent will pass on the mutation to some or all of its offspring.
MDR1 is an autosomal dominant genetic disorder, which means that only one copy of the gene is necessary for the dog to be affected. There is therefore no such thing as an MDR1 carrier. While dogs with two mutant genes (homozygous) are more severely impacted by the mutation, dogs with one mutant and one normal gene (heterozygous) are still at risk of adverse effects from common veterinary drugs. Washington State University’s PrIMe Laboratory is the leader in MDR1 research in the United States, and has a list of veterinary drugs affected by MDR1 available by clicking on this link. Importantly, drugs affected by MDR1 are the antihelminthics of the ivermectin family. While these drugs are known to be safe at levels used to prevent heartworm disease, higher doses such as the ones used to treat mange have lead to neurotoxic effects. Other examples of drugs to look out for are loperamide (immodium), cyclosporine and many chemotherapeutic agents.
Symptoms of MDR1-related neurotoxicity include weakness, lethargy, ataxia (loss of coordination), disorientation, tremors, seizures, blindness, and death. If you notice any of these symptoms, contact your veterinarian immediately.
The Collie Health Foundation has been proudly funding research into MDR1 since 1989 and subsidizes MDR1 DNA tests for rough and smooth collies owned by CHF members. More information here!
MDR1 Genetic Results and their Meaning
Normal/Normal – These dogs do not carry the mutation, and will not pass on the mutation to their offspring. These dogs would not be expected to experience unexpected adverse drug reactions to normal doses of ivermectin, loperamide (Imodium) and some anticancer drugs.
Mutant/Mutant – These dogs carry the mutation and will pass on the mutant gene to all their offspring. These dogs would be expected to experience toxicity after normal doses of loperamide (Imodium), some anticancer drugs, and high doses of ivermectin (greater than 50 micrograms per kilogram.)
Mutant/Normal – These dogs carry the mutation and will pass on the mutant gene to some of their offspring. These dogs may experience toxicity after normal doses of loperamide (Imodium), some anticancer drugs, and high doses of ivermectin (greater than 50 micrograms per kilogram.)
Wanting to test your collie? Request test codes for Optimal Selection (for breeders) or Washington State University (for pets)!
|Drug Active Ingredient||Brand Name||Use||Recommendation|
|Acepromazine||Tranquilizer||Contact WSU for dose recommendation.|
|Afoxolaner||Nexgard||Flea & Tick||No adverse effects were observed. Dogs with the MDR1 mutation are not at increased risk for adverse effects.|
|Apomorphine||Induce vomiting||Contact WSU for dose recommendation.|
|Butorphanol||Torbugesic||Anesthetic||Contact WSU for dose recommendation.|
|Cyclosporine||Atopica||Dermatitis||Contact WSU for dose recommendation.|
|Doxorubicin||Chemotherapy||Contact WSU for dose recommendation.|
|Fluralaner||Bravecto||Flea & Tick||No adverse effects were observed. Dogs with the MDR1 mutation are not at increased risk for adverse effects.|
|Grapiprant||Galliprant|| Pain & Inflammtion||Contact WSU for dose recommendation.|
|Ivermectin||Heartgard||Heartworm||The FDA has determined Heartgard is safe for dogs with the MDR1 mutation when used at label doses.|
|Loperamide||Immodium||Diarrhea||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.|
|Maropitant||Cerenia||Vomiting||Contact WSU for dose recommendation.|
|Moxidectin||ProHeart|| Heartworm||The FDA determined ProHeart is safe for dogs with the MDR1 mutation when used at label doses.|
|Ondansetron||Zofran||Vomiting||Contact WSU for dose recommendation.|
|Sarolaner||Simparica||Flea & Tick||No adverse effects were observed. Dogs with the MDR1 mutation are not at increased risk for adverse effects.|
|Vinblastine||Chemotherapy||Contact WSU for dose recommendation.|
|Vincristine||Chemotherapy||Contact WSU for dose recommendation.|
|Vinorelbine||Chemotherapy||Contact WSU for dose recommendation.|
|Selamectin||Revolution||Flea, Tick & Heartworm||The FDA determined Revolution is safe for dogs with the MDR1 mutation when used at label doses.|
Table adapted from WSU PrIMe: https://prime.vetmed.wsu.edu/2022/03/01/problem-medications-for-dogs/
MDR1 is a gene that codes for a P-glycoprotein (P-gp) that acts as an exhaust pump. When working correctly, this exhaust pump plays an important role in the distribution of drugs inside the body. P-gp is an intrinsic part of the blood-brain barrier, a natural protection of the brain against circulating toxins or pathogens.
In dogs where the MDR1 mutation is present, a deletion of four bases in the DNA severely truncates the P-glycoprotein, rendering it non-functional. In consequence, drugs can pass through normally impermeable barriers in the body, such as the blood-brain barrier, and accumulate in the brain. This is the cause of the neurological symptoms seen in MDR1 dogs exposed to problem drugs. Interestingly, the MDR1 mutation can be traced a dog that lived in Great Britain before different herding breeds were isolated genetically by closing stud books (ca. 1873).
MDR1 doesn’t just affect the brain. P-gp is also present in dogs’ guts, liver and kidneys. In the gut, P-gp restricts absorption of drugs while, in the liver and kidneys, it promotes their excretion. MDR1 mutant dogs therefore absorb more and excrete less drugs than their unaffected counterparts.
Recent research has shown that MDR1 status also affects cortisol metabolism and could contribute to disruption of hypothalamic–pituitary–adrenal axis regulation, and be a factor in developing Addison’s disease.
Washington State University PrIMe Lab: https://prime.vetmed.wsu.edu/
Neff, M. W., Robertson, K. R., Wong, A. K., Safra, N., Broman, K. W., Slatkin, M., Mealey, K. L., & Pedersen, N. C. (2004). Breed distribution and history of canine mdr1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proceedings of the National Academy of Sciences USA, 101(32), 11725–11730. https://doi.org/10.1073/pnas.0402374101
Geyer, J., & Janko, C. (2012). Treatment of MDR1 mutant dogs with macrocyclic lactones. Current Pharmaceutical Biotechnology, 13(6), 969–986. https://doi.org/10.2174/138920112800399301
Gramer, I., Karakus, E., Hartmann, M. F., Wudy, S. A., Bauer, N., Moritz, A., Aktürk, Z., & Geyer, J. (2022). Urinary cortisol metabolites are reduced in MDR1 mutant dogs in a pilot targeted GC-MS urinary steroid hormone metabolome analysis. Journal of Veterinary Pharmacology and Therapeutics, 45, 265– 272. https://doi.org/10.1111/jvp.13050