Ivermectin dominates conversations about MDR1 drug sensitivity, and for good reason. It is the most commonly implicated drug in toxicity cases I see. But ivermectin is just one member of a larger drug family called the macrocyclic lactones. Every drug in this family interacts with P-glycoprotein. Every one of them can potentially cause problems in MDR1-affected dogs, though the degree of risk varies significantly.
Understanding the entire drug family matters because these medications appear under many brand names in products ranging from heartworm preventatives to flea treatments to livestock dewormers. An owner who knows to avoid ivermectin might not recognize that the cattle drench in the barn contains doramectin, or that their dog's topical flea preventative contains selamectin. Both are macrocyclic lactones.
The Macrocyclic Lactone Family
Macrocyclic lactones are divided into two structural subgroups. The avermectins include ivermectin, selamectin, doramectin, and abamectin. The milbemycins include milbemycin oxime and moxidectin. All of these drugs share a similar mechanism of action: they bind to glutamate-gated chloride channels in invertebrate neurons, causing paralysis and death. This makes them highly effective antiparasitic agents.
The reason mammals normally tolerate these drugs is P-glycoprotein. This efflux pump keeps macrocyclic lactones out of the central nervous system where they could cause the same paralysis they induce in parasites. Remove that pump through MDR1 mutation, and the drugs gain access to receptors throughout the brain and spinal cord.
The drugs differ in their lipophilicity, their affinity for P-glycoprotein, their pharmacokinetics, and consequently their safety profiles in MDR1-affected dogs. Let me walk through each one.
Ivermectin: The Most Dangerous
Ivermectin remains the most frequently implicated macrocyclic lactone in toxicity cases. This is partly because it is extremely common. Ivermectin is used in heartworm preventatives (Heartgard, Iverhart, Tri-Heart), in livestock products (Ivomec, various generics), and was historically used at high doses for mange treatment.
The problem with ivermectin is the enormous range of doses encountered. Heartworm prevention uses 6 micrograms per kilogram monthly. Mange treatment used 300 to 600 micrograms per kilogram daily. Livestock products deliver doses that can exceed 2000 micrograms per kilogram when a dog ingests them.
At heartworm prevention doses, ivermectin has an acceptable safety record even in MDR1-affected dogs. The danger lies in higher doses, whether from intentional treatment decisions or accidental ingestion of concentrated livestock products.
Ivermectin Products to Know
Canine Heartworm Prevention: Heartgard, Heartgard Plus, Iverhart Plus, Iverhart Max, Tri-Heart Plus
Livestock: Ivomec (injectable, pour-on, paste), Noromectin, Bimectin, Eqvalan (horse), and numerous generic formulations
Risk Level: Low at prevention doses, high to extreme at therapeutic or livestock doses
Milbemycin Oxime: The Safer Choice
Milbemycin oxime has the best safety profile among the macrocyclic lactones for MDR1-affected dogs. It is a less potent P-glycoprotein substrate than ivermectin, meaning more of the drug is pumped out of the brain even in dogs with reduced P-glycoprotein function.
Studies have tested milbemycin at three to five times the label dose in MDR1-affected Collies without observing adverse effects. This provides a meaningful safety margin that does not exist with ivermectin at higher doses.
Milbemycin is found in heartworm preventatives like Interceptor, Interceptor Plus, and Sentinel. It is also combined with spinosad in Trifexis. All of these products have demonstrated good safety in MDR1-affected dogs when used at label doses.
For my MDR1-affected patients who need monthly heartworm prevention, milbemycin products are my first recommendation. The combination products that add flea control or intestinal parasite coverage are reasonable options depending on the dog's lifestyle and exposure risks.
Milbemycin Oxime Products
Canine Products: Interceptor, Interceptor Plus, Sentinel, Sentinel Spectrum, Trifexis, Milbehart
Prevention Dose: 0.5-1 mg/kg monthly
Safety in MDR1 Dogs: Excellent at label doses. Studies show safety up to 5x label dose in affected Collies.
Recommendation: Preferred choice for MDR1-affected dogs needing heartworm prevention
Moxidectin: Proceed with Caution
Moxidectin occupies a middle ground. It is more lipophilic than milbemycin, which means it penetrates fatty tissues including the brain more readily. Some research suggests it may have a narrower safety margin in MDR1-affected dogs compared to milbemycin.
The topical formulation (Advantage Multi, also called Advocate in some countries) applies moxidectin to the skin for absorption. It provides heartworm prevention plus control of fleas, hookworms, roundworms, and whipworms. At label doses, most MDR1-affected dogs tolerate this product, but I have seen occasional reports of adverse effects.
ProHeart 6 and ProHeart 12 are the injectable moxidectin formulations that provide six or twelve months of heartworm prevention from a single injection. These products concern me in MDR1-affected dogs because of the prolonged drug release. If an adverse reaction occurs, there is no way to remove the drug from the body. It will continue releasing for months.
A few years ago I treated a German Shepherd who had received ProHeart 12 without anyone questioning whether MDR1 testing should have been done first. He developed signs of toxicity about two weeks after injection. We could provide supportive care, but we could not stop the ongoing drug release. He survived, but his recovery was prolonged and complicated. That case cemented my policy of not recommending ProHeart products for dogs with known or suspected MDR1 mutations.
Selamectin: Generally Safe
Selamectin, found in Revolution and Revolution Plus, is structurally distinct from ivermectin despite being in the avermectin subgroup. Studies have demonstrated good safety at multiples of the label dose in MDR1-affected dogs.
Revolution is applied topically and provides heartworm prevention plus flea, tick, ear mite, and certain intestinal parasite control. The broad coverage makes it convenient for many owners. The minimum dose is 6 mg/kg.
I consider selamectin a reasonable option for MDR1-affected dogs. It has a track record of safe use in sensitive breeds and provides comprehensive parasite protection. If an owner prefers a topical product over monthly oral medication, Revolution is preferable to Advantage Multi in my opinion. For a complete discussion of safe options, see our guide to safe heartworm prevention.
Doramectin: High Risk
Doramectin is primarily used in cattle (Dectomax). It is more potent than ivermectin and has a longer half-life. Dogs should never be intentionally treated with doramectin, and exposure to cattle products containing doramectin carries significant toxicity risk.
I have treated two doramectin toxicity cases in my career. Both were dogs who had access to cattle facilities. One ingested injectable doramectin that had been improperly stored. The other was a working dog who was accidentally dosed when someone confused dog and cattle dewormers. Both cases were severe. One dog survived after prolonged intensive care. One did not.
Doramectin has no place in canine medicine. If you have this product on your property and you have dogs, secure it completely.
Abamectin: Agricultural Hazard
Abamectin is used primarily in agriculture as an insecticide and miticide. It is found in ant bait stations, some crop protection products, and livestock external parasite treatments. Dogs are occasionally exposed through ingestion of bait stations or contact with treated animals.
Abamectin toxicity presents similarly to ivermectin toxicity. Treatment is supportive. The main clinical message is awareness: if a dog has access to areas where abamectin products are used, exposure is possible. MDR1-affected dogs face elevated risk from even relatively small exposures.
Eprinomectin: Limited Canine Data
Eprinomectin is used in cattle (Eprinex, LongRange) and has minimal documented canine exposure. It is structurally similar to ivermectin and should be assumed to carry similar risks in MDR1-affected dogs. Keep livestock products containing eprinomectin secured away from dogs.
A Comparative Risk Assessment
Based on available evidence and clinical experience, here is how I rank the macrocyclic lactones for risk in MDR1-affected dogs:
| Drug | Risk Level | Clinical Notes |
|---|---|---|
| Milbemycin oxime | Lowest | Preferred for MDR1 dogs at label doses |
| Selamectin | Low | Good safety record in sensitive breeds |
| Ivermectin (prevention dose) | Low-Moderate | 6 mcg/kg monthly generally tolerated |
| Moxidectin (topical) | Moderate | Monitor after application |
| Moxidectin (injectable) | Moderate-High | Not recommended due to prolonged release |
| Ivermectin (high dose) | High | Never use extra-label doses in MDR1 dogs |
| Doramectin | Very High | No canine indication, severe toxicity risk |
| Abamectin | High | Agricultural product, accidental exposure concern |
Beyond the Macrocyclic Lactones
While this article focuses on macrocyclic lactones, MDR1-affected dogs face risks from other P-glycoprotein substrate drugs as well. Loperamide (Imodium) causes neurotoxicity in affected dogs at doses that are safe for normal dogs. Certain chemotherapy agents, acepromazine, and butorphanol also interact with P-glycoprotein.
The Washington State University Veterinary Clinical Pharmacology Laboratory maintains a comprehensive list of drugs that require caution in MDR1-affected dogs. I recommend this resource for both veterinarians and owners who want the complete picture. For foundational information about the MDR1 mutation and its inheritance, the MDR1 genetics guide at The Herding Gene offers thorough coverage.
Practical Recommendations
For dog owners and breeders in at-risk breeds, here are my practical recommendations regarding macrocyclic lactones:
First, test your dog. MDR1 testing is inexpensive, widely available, and provides information that guides medication decisions for your dog's entire life.
Second, choose heartworm preventatives thoughtfully. For MDR1-affected dogs, I recommend milbemycin products (Interceptor, Sentinel) as first choice. Selamectin (Revolution) is a reasonable alternative. Ivermectin at prevention doses is acceptable but offers no advantage. Avoid ProHeart injectable products.
Third, secure all macrocyclic lactone products. This includes livestock dewormers (ivermectin, doramectin), horse paste wormers, cattle pour-ons, and any concentrated formulations. A curious dog can ingest a lethal dose in seconds. Prevention is everything.
Fourth, communicate your dog's MDR1 status to everyone who provides care. Veterinarians, boarding facilities, groomers, and pet sitters should all know. Put it in writing. Put it on your dog's collar. Make it impossible to miss.
Fifth, if accidental exposure occurs, seek veterinary care immediately. Early decontamination and supportive treatment dramatically improve outcomes. Do not wait to see if symptoms develop. For guidance on recognizing toxicity, see our clinical signs guide and treatment protocol.
Looking Forward
Research continues on macrocyclic lactone safety and on understanding the nuances of P-glycoprotein function in different species and individuals. New antiparasitic drugs from different drug classes may eventually provide alternatives that completely avoid MDR1 concerns.
For now, the macrocyclic lactones remain essential tools in veterinary medicine. They are effective, generally safe when used correctly, and irreplaceable for certain applications. Our job is to use them wisely, understand their risks, and protect the dogs who are genetically vulnerable.
The MDR1 mutation is a manageable condition. Dogs with this mutation can live full, healthy lives with appropriate precautions. But those precautions require knowledge, and that knowledge must extend beyond ivermectin to the entire macrocyclic lactone family. Now you have that knowledge. Use it to keep your dogs safe.