As our understanding of genetics has grown, veterinarians have increasing opportunities to educate clients about potential breed-specific concerns and counsel on genetic testing opportunities. One notable genetic mutation that can lead to significant neurological toxicity and even death from certain drugs is the MDR1 mutation.

Veterinarians should be aware of which patients should be tested for this mutation and how to manage their medications.

Understanding the genetics

The MDR1 gene (also known as the ABCB1 gene) encodes P-glycoprotein, a drug transporter located at the blood-brain barrier and other tissues that prevents certain drugs from entering the nervous system.^1,2

Ivermectin sensitivity was observed in some collies, leading to researchers to investigate a possible genetic basis. A 4-base pair deletion was identified in the MDR1 gene by Katrina Mealey, DVM, PhD, DACVCP, DACVIM, and colleagues in 2001.¹ This mutation causes protein synthesis to stop prematurely, leading to a nonfunctional drug transporter.¹

Patients that are homozygous for this mutation are affected by sensitivity to multiple drugs. When exposed to these drugs, clinical signs can vary from weakness, ataxia, and tremors, to seizures, blindness, and death.

The mutation should be suspected in at-risk breeds and any patient that has a reaction to a drug known to be a substrate of P-glycoprotein. Additionally, these drugs have less biliary excretion, due to the presence of the P-glycoprotein molecule in the bile ducts, causing decreased clearance of some drugs.³

Knowing the MDR1 genotype of a patient allows veterinarians to adjust their treatment plans. A genetic test is available through Washington State University’s Program for Individualized Medicine (PRiME).⁴ Test kits can be ordered by clients or veterinarians, and samples can be obtained by cheek swab or blood draw.

Which patients are at risk?

The MDR1 mutation is often associated with herding breeds, such as collies, Australian shepherds, and Shetland sheepdogs. The mutation is most prevalent in collies (up to 70%).^1,4 Up to 50% of other herding breeds will have the mutation.^2,3

However, the mutation has also been identified in several other breeds, including German shepherd (10%), English shepherd (15%), Silken Windhound (30%), McNab (30%), and Long-Haired Whippet (65%).^2,3 Testing should be considered for dogs of these breeds.

Up to 10% of mixed breed dogs can also be affected.³ It is important to note that even dogs that do not obviously look like herding breed mixes can be homozygous for the mutation.² It may be prudent to discuss testing with owners of all mixed breed dogs prior to administering a medication known to be a P-glycoprotein substrate.

Cats can also have a mutation. First identified in 2015, this mutation is a nonsense mutation of the same gene.⁵ It is present in up to 4% of the feline population.³

Drugs of concern for MDR1 mutations

The MDR1 mutation was first discovered because of observed ivermectin sensitivities. Ivermectin and related drugs are safe at doses used for heartworm prevention but can become toxic at doses used to treat mange.^3,6

Manufacturers of drugs containing alfaxolaner, fluralaner, ivermectin, milbemycin, moxidectin, sarolaner, and selamectin have tested these drugs for safety in patients with MDR1 mutations and are deemed safe at FDA-approved doses.^3,5

A full list of drugs that can be problematic for patients with the MDR1 mutation is available through WSU’s PRiME.

These drugs include:

• Certain anesthetic agents (butorphanol and acepromazine)
• Antiemetics (maropitant, ondansetron)
• Apomorphine
• Grapiprant
• Cyclosporine
• Some chemotherapy agents^3,6

Identification of these drugs comes from prospective studies, retrospective studies, case reports, and some anecdotal information.³ In cats, case reports of sensitivities to eprinomectin and ivermectin have been published.³

When possible, choosing an alternative drug to accomplish the same therapeutic effect is recommended in patients with known or suspected MDR1 mutations. When this is not possible, dosing recommendations for individual patients are available through a consultation with Washington State University College of Veterinary Medicine’s PRiME.

References and resources

1. Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2011;11(8):727-733.
2. Mealey KL & Meurs KM. Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. Journal of the American Veterinary Medical Association2008;233(6)921-924. https://doi.org/10.2460/javma.233.6.921
3. Mealey KL, Owens JG & Freeman E.  Canine and feline P-glycoprotein deficiency: What we know and where we need to go. Journal of Veterinary Pharmacology and Therapeutics, 2023;46:1–16. https://doi.org/10.1111/jvp.13102
4. Washington State University. MDR1 testing for your patients. Published . Available at https://prime.vetmed.wsu.edu/for-veterinarians/. Accessed November 10, 2023.
5. Mealey KL & Burke NS. Identification of a nonsense mutation in feline ABCB1. Journal of Veterinary Pharmacology and Therapeutics, 2015;38:429–433. https://doi.org/10.1111/jvp.12212
6. Washington State University. Problem medications for dogs. Published March 1, 2022. Available at https://prime.vetmed.wsu.edu/2022/03/01/problem-medications-for-dogs/. Accessed November 10, 2023.

Kate Boatright, VMD, is a small animal veterinarian, speaker, and author in western Pennsylvania. She graduated from the University of Pennsylvania in 2013 and has worked in rural small animal general practice and emergency clinics ever since. She is passionate about inciting positive change in the profession through mentorship and servant leadership in organized veterinary medicine.

Photo credit:  © smrm1977  E+ via Getty Images Plus

Disclaimer: The views expressed, and topics discussed, in any NEWStat column or article are intended to inform, educate, or entertain, and do not represent an official position by the American Animal Hospital Association (AAHA) or its Board of Directors.