A History of MDR1

By Dr. Roxane Jourdain

Published in the 2025 Spring Edition of the Collie Club of America Bulletin

MDR1, or Multidrug Resistance 1, is a well-known genetic mutation in dogs that affects the body’s natural barriers. As Collie owners, breeders, and lovers, we are keenly aware of this mutation’s influence on our dogs’ health. Many breeders tell buyers to avoid using products like ivermectin on their dogs regardless of whether the dog has been tested. This article is a retrospective on the history of MDR1, and how we can use the tools we have in hand today to improve the health of our breed.

The protein that is changed by the MDR1 mutation was first found in 1976 to be P-glycoprotein, a molecular bilge pump that sits on the cell’s surface^[i]. When cancer cells were cultured with increasing amounts of a single anticancer drug, they acquired resistance to unrelated drugs without any prior exposure. The source of the resistance was traced back to P-glycoprotein, and, because of this, the gene encoding it was named Multidrug Resistance 1, or MDR1.^[ii] Later, the gene name was changed to ABCB1, and both notations are still used today. This protein is present in all living organisms, from bacteria to mammals. In its normal function, it acts as a gatekeeper. It limits the absorption of drugs through the gut, and protects the brain, forming the blood-brain barrier.

The initial link between the MDR1 gene and antiparasitic medication was identified in 1994 after a mouse was engineered to lack the MDR1 gene.^[iii] Initially, researchers were surprised to see the mice were healthy, fertile, and appeared to have a normal lifespan. The interest in MDR1 would have waned if not for a serendipitous mite infestation. The infected mice were sprayed with ivermectin according to the lab’s standard procedure. Within 24 hours, nearly all the MDR1-lacking mice had died. Postmortem studies showed that the concentration of ivermectin in those mice’s brains was 100-fold higher than in normal mice. This chance discovery kickstarted the study of MDR1 mutations’ effect on pharmaceutical agents.

A sensitivity to ivermectin similar to that seen in MDR1-lacking mice was reported in Collies and other herding breeds in the 1980s.^[iv] After the 1995 ivermectin mouse incident, researchers surmised that a mutation of the MDR1 gene could cause this sensitivity – the same seen in the mice lacking the MDR1 gene. In 2001, this sensitivity was tracked by Dr Katrina Mealey of Washington State University to a small mutation in the MDR1 gene – a deletion of four DNA base pairs named MDR1-1Δ.^[v]

This small change in the MDR1 gene sequence has huge implications: the production of P-glycoprotein is stopped early. The bilge pump protecting the brain is broken and cannot prevent potentially toxic compounds from entering. MDR1-1Δ-affected dogs thus experience adverse effects when exposed to high doses of ivermectin, or similar drugs in its family such as milbemycin (Interceptor), selamectin (Revolution), and moxidectin (Advantage). Similarly, adverse effects were observed with loperamide, an opioid used to treat diarrhea.^[vi] Without functional P-glycoprotein, dogs with the MDR1-1Δ mutation are not protected and can develop neurological symptoms such as ataxia, rear limb weakness, and disorientation.

The canine MDR1-1Δ mutation was traced to a single dog that lived in Great Britain before the registration of individual breeds began in 1873.^[vii] It is found in several dog breeds, such as Australian Shepherds, Shetland Sheepdogs, and Border Collies. However, they are not exclusive to dogs. Similar gene mutations have been identified in mice,^[viii] humans,^[ix] cats,^[x] and recently goats.^[xi]

Many drugs can be affected by these mutations, and it’s hard to know if a new drug will be a problem for dogs with the MDR1-1Δ mutation. Problem drugs include cancer treatments like vinblastine and immune system drugs like cyclosporine. FDA approval requires that drugs used for humans must be tested for MDR1 sensitivity, but, that is not the case for veterinary drug candidates. Therefore, testing new drugs used in veterinary medicine is essential to prevent adverse effects in MDR1-1Δ affected dogs.

The Collie Health Foundation has a vested interest in funding projects benefiting the future health of the Collie. Since Dr. Mealey discovered the MDR1-1Δ mutation, the CHF has provided $86,000 in grants to Washington State University to study how new drugs might affect dogs with this mutation. Thanks to this funding, precise dosage protocols for MDR1 problem drugs are now available through the WSU Program in Individualized Medicine (PrIMe).

Recently, Dr. Mealey published a method allowing her to test potential MDR1 drugs without having to administer them to affected dogs, using a cultured cell line instead.^[xii] The development of this technology would allow the rapid and high throughput testing of new veterinary drugs. For example, the lymphoma drug verdinexor was found in 2023 to be safe for MDR1-1Δ dogs.^[xiii] Additionally, an ongoing CHF-funded project at Iowa State University by Dr. Bonnie L Hay Kraus is investigating modified sedation and anesthesia protocols for increased safety in MDR1-1Δ affected dogs.

Supporting and participating in these research projects is vital for the health of our dogs. 75% of Collies carry at least one copy of the MDR1-1Δ mutation. While these dogs live healthy lives with no decrease in lifespan, we mustn’t cause a genetic bottleneck by stopping breeding these dogs altogether. Instead, we can use reliable DNA testing to make informed breeding decisions, ensuring we maintain the breed’s valuable traits while managing, and hopefully decreasing, the frequency of the MDR1-1Δ mutation.

As caretakers of this beloved breed, we have a dual responsibility. First, we need to work towards reducing the prevalence of the MDR1-1Δ mutation over time. Second, we must ensure that we have effective protocols to treat dogs affected by this mutation. This means staying informed about new research and supporting initiatives to improve our dogs’ health and well-being.

If you’re interested in joining CHF-funded research projects or want to learn more about how you can help, we encourage you to visit our website. Your involvement can make a significant difference in the health and future of our Collies.

https://www.colliehealth.org/grants-samples/research-samples-needed/

To stay current on MDR1 Problem Drugs, we recommend you save and regularly check the Washington State University PrIMe website. PrIMe can also help give veterinarians dose recommendations for these problem drugs.

https://prime.vetmed.wsu.edu/2022/03/01/problem-medications-for-dogs/

References:

^[i] Juliano, R. L., & Ling, V. (1976). A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica et Biophysica Acta (BBA) – Biomembranes, 455(1), 152-162. https://doi.org/10.1016/0005-2736(76)90160-7

^[ii] Ueda, K., Cardarelli, C., Gottesman, M. M., & Pastan, I. (1987). Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proceedings of the National Academy of Sciences, 84(9), 3004-3008. https://doi.org/10.1073/pnas.84.9.3004

^[iii] Schinkel, A. H., Smit, J. J. M., van Tellingen, O., Beijnen, J. H., Wagenaar, E., van Deemter, L., Mol, C. A. A. M., van der Valk, M. A., Robanus-Maandag, E. C., te Riele, H. P. J., Berns, A. J. M., & Borst, P. (1994). Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell, 77(4), 491-502. https://doi.org/10.1016/0092-8674(94)90212-7

^[iv] Paul, A., Tranquilli, W., Seward, R., Todd Jr, K., & DiPietro, J. (1987). Clinical observations in collies given ivermectin orally. American Journal of Veterinary Research, 48(4), 684-685.

^[v] Mealey, K. L., Bentjen, S. A., Gay, J. M., & Cantor, G. H. (2001). Ivermectin sensitivity in collies is associated with a deletion mutation of the MDR1 gene. Pharmacogenetics and Genomics, 11(8), 727-733. https://journals.lww.com/jpharmacogenetics/fulltext/2001/11000/ivermectin_sensitivity_in_collies_is_associated.12.aspx

^[vi] Sartor, L. L., Bentjen, S. A., Trepanier, L., & Mealey, K. L. (2004). Loperamide Toxicity in a Collie with the MDR1 Mutation Associated with Ivermectin Sensitivity. Journal of Veterinary Internal Medicine, 18(1), 117-118. https://doi.org/10.1111/j.1939-1676.2004.tb00145.x

^[vii] 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, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proceedings of the National Academy of Sciences, 101(32), 11725-11730. https://doi.org/doi:10.1073/pnas.0402374101

^[viii] Lankas, G. R., Cartwright, M. E., & Umbenhauer, D. (1997). P-Glycoprotein Deficiency in a Subpopulation of CF-1 Mice Enhances Avermectin-Induced Neurotoxicity. Toxicology and Applied Pharmacology, 143(2), 357-365. https://doi.org/10.1006/taap.1996.8086

^[ix] eiri, I., Takane, H., & Otsubo, K. (2004). The MDR1 (ABCB1) Gene Polymorphism and its Clinical Implications. Clinical Pharmacokinetics, 43(9), 553-576. https://doi.org/10.2165/00003088-200443090-00001

^[x] Mealey, K. L., & Burke, N. S. (2015). Identification of a nonsense mutation in feline ABCB1. Journal of Veterinary Pharmacology and Therapeutics, 38(5), 429-433. https://doi.org/10.1111/jvp.12212

^[xi] Nürnberger, D., Müller, S. F., Hamann, M., & Geyer, J. (2021). First Sequencing of Caprine MDR1 (ABCB1) mRNA Due to Suspected Neurological Adverse Drug Reaction in a Thuringian Goat Following Extra-Label Use of Doramectin. Frontiers in Veterinary Science, 8, 682393. https://doi.org/10.3389/fvets.2021.682393

^[xii] Mealey, K. L., Dassanayake, S., & Burke, N. S. (2017). Establishment of a cell line for assessing drugs as canine P-glycoprotein substrates: proof of principle. Journal of Veterinary Pharmacology and Therapeutics, 40(5), 545-551. https://doi.org/10.1111/jvp.12390

^[xiii] Mealey, K. L., & Burke, N. S. (2023). Assessment of verdinexor as a canine P-glycoprotein substrate. Journal of Veterinary Pharmacology and Therapeutics, 46(4), 264-267. https://doi.org/10.1111/jvp.13123