Drug Sensitivity in Collies:

MDR1 mutation

NorCal Collie Rescue brings you the latest research on drug sensitivity in Collies.

This research is being conducted at Washington State University, by Dr. Katrina Mealey and at the University of California Davis Veterinary Genetics Laboratory by Dr. Mark Neff and his team of researchers. 


General summary:

* Click here for your own Collie Drug sensitivity form to take to your veterinarian.



Technical summary for veterinarians:

Four unrelated pet Collies in one household

• Sensitivity of Collies to certain pharmaceuticals, in particular for treatment of heartworm and mites (ivermectin), is now known to be caused by a genetic defect in the mechanism that prevents drugs from building up in the brain.

• This mutation is recessive and is called mdr1-1Δ.  The normal gene that protects the brain is called MDR1.

• A test for this mutation is now commercially available.

• Research shows that 1 in 3 or 4 Collies in the U.S. is "pure" for the mutation.  These Collies suffer acute and often fatal neurotoxicosis when certain drugs are administered at higher doses in treatment and prevention of heartworm, and this may also apply to other ailments (see below). 

• An additional 50% of Collies carry the mdr1-1Δ gene and may also be susceptible to toxic effects when certain drugs are administered at normally therapeutic doses.  Only 1 in 5 Collies on average is "pure" for normal for the MDR1 gene and therefore can tolerate these drugs at therapeutic doses .

• Two common medications administered in an oral monthly tablet for prevention of heartworm (ivermectin and milbemycin oxime) have been given to Collies "pure" for the mutation mdr1-1Δ without incident. These two forms of heartworm prophylaxis are equally safe at the monthly prophylaxis dose, and both are toxic at higher doses. 

• At least one published study confirms anecdotes that moxidectin (used in the 6-month injection for heartworm prevention) can cause acute and sometimes fatal neurotoxicosis in susceptible Collies.

• So-called "ivermectin" sensitivity is actually sensitivity to a broad class of compounds due to a basic defect in the blood-brain barrier.  Normal dogs are protected from acute and often fatal neurotoxicoses when these compounds are administered as pharmaceuticals (including ivermectin) by P-glycoprotein, an ATP-dependent drug transporter that moves a broad spectrum of substrates across several tissue borders throughout the body.  The normal gene encoding for P-glycoprotein is MDR1.

• A mutation in MDR1 called mdr1-1Δ causes defects in the coding for P-glycoprotein that result in nearly complete loss of its function.  More than 20 therapeutic drugs are known substrates of P-glycoprotein.  At least several are now known to cause toxic reactions in Collies with at least one mdr1-1Δ allele. 

• Approximately 1 in 3 or 4 Collies in the United States are homozygous for the mdr1-1Δ mutation. These Collies are particularly sensitive to drugs that are substrates for P-glycoprotein and will suffer acute and often fatal neurotoxicosis when normally therapeutic levels of these drugs are administered. 

• In addition, half of the Collies in the US carry the mdr1-1Δ mutation (are heterozygous) and may be sensitive to therapeutic doses of these drugs, depending on the drug.  The drugs listed below should be administered to heterozygous dogs with caution. 

• Only 1 in 5 Collies are homozygous for the normal form of this gene, MDR1. 

• Anti-helminthic pharameuticals that are P-glycoprotein substrates include the family of compounds known as macrocyclic lactones.  These compounds exert their anti-helminthic properties by causing neurotoxicosis in a number of invertebrates (including helminths and arthropods) by potentiating ligand-gated chloride ion channels in the peripheral nervous system.   Generations of macrocyclic lactones known as avermectins have been developed for veterinary use, decreasing their toxic side effects to normal animals (without the mdr1-1Δ mutation). 

• These compounds include:  ivermectin, milbemycin oxime, moxidectin, selamectin, and doramectin. 

• Collie owners have long known that ivermectin in the treatment of helminths and mites can result in death of some Collies.  Until the mutation and its frequency were discovered, the inconsistency in toxic reaction within the breed caused some confusion.  Now we know that approximately 30% of collies are homozygous for the mutation, and these are the Collies particularly at risk.  Because a commercial test is now available, purebred Collies should be genetically tested before administering any drug that is a P-glycoprotein substrate in high doses. 

• Given the mechanism for toxcity, there is no reason to consider milbemycin oxime safer for dogs with the mdr1-1Δ mutation than ivermectin. The monthly oral dose of both ivermectin and milbemycin oxime has been administered for heartworm prophylaxis to Collies homozygous for mdr1-1Δ without incident and both have been shown to have similar pharmaceutical margins of safety in sensitive Collies (Tranquilli et al. 1991).

• Higher doses of moxidectin, including the 6-month injection for heartworm prophylaxis, have been tied to reports of acute neurotoxicosis and death in some Collies.  Although research on this form of heartworm prophylaxis is equivocal, one published study documents acute neurotoxicosis in an apparently sensitive (homozygous) Collie, so this form of heartworm prophylaxis may be risky for Collies that have not been tested for presence of the mutation mdr1-1Δ. [Note:  the 6-month injection has been recalled because of defects in the time-release mechanism, which was likely responsible for the collie deaths]

• The topical application of selamectin for heartworm prevention has been linked anecdotally to the death of an Australian shepherd (see below for a list of breeds also known to possess the mdr1-1Δ mutation).  However, topical selamectin when administered according to the labeling has been used on sensitive Collies without incident. 

• Examples of other drugs that are P-glycoprotein substrates include:  erythromycin, grepafloxacin (antimicrobial agents); doxorubicin, vinca alkaloids, e.g., vincristine, vinblastine (anticancer agents); cyclosporin A, tacrolimus (immunosuppressants); dexamethasone, hydrocortisone (steriods); loperamide, domperidon (gastrointestinal drugs); and quinidine, digoxin (cardiac drugs), acepromazine (tranquilizer), butorphanol (pain control).

• Drugs known or suspected to be P-glycoprotein substrates and therefore should be used with caution on sensitive Collies include:  ondansetron, domperidone, paclitaxel, mitoxantrone, etoposide, rifampicin, morphine. 

• Biochemical studies have shown that over 50 different drugs may be affected by the mdr1-1Δ mutation when administered to sensitive Collies. 

• Collies exhibit the highest frequency by far of the mdr1-1Δ mutation, with 3 of 4 collies possessing at least one mdr1-1Δ allele.  Many of the common dog breeds have been tested.  So far the mdr1-1Δ mutation has been found (in lower frequencies) in Australian Shepherds, English Shepherds, Shetland Sheepdogs, Old English Sheepdogs, McNabs, Long-haired Whippets, and Silken Windhounds. 

Proceedings of the National Academy of Sciences USA 2004 101:11725-30. Breed distribution and history of mdr1-1Δ, a pharmacogenetic mutation that marks the emergence of formal breeds from the collie lineage. Mark W. Neff, Kathryn R. Robertson, Aaron Wong, Noa Safra, Karl W. Broman, Montgomery Slatkin, Katrina L. Mealey, and Niels C. Pedersen.

 

ABSTRACT:  A mutation in the canine multidrug resistance gene, MDR1, has previously been associated with drug sensitivities in two breeds from the collie lineage. We exploited breed phylogeny and reports of drug sensitivity to survey other purebred populations that might be genetically at risk. We found that the same allele, mdr1-1, segregated in seven additional breeds, including two sighthounds that were not expected to share collie ancestry. A mutant haplotype that was conserved among affected breeds indicated that the allele was identical by descent. Based on breed histories and the extent of linkage disequilibrium, we conclude that all dogs carrying mdr1-1 are descendants of a dog that lived in Great Britain before the genetic isolation of breeds by registry (ca. 1873). The breed distribution and frequency of mdr1-1 have applications in veterinary medicine and selective breeding, whereas the allele's history recounts the emergence of formally recognized breeds from an admixed population of working sheepdogs.  Click here to obtain the article from PNAS.

Am J Vet Res. 2002 Apr;63(4):479-81.
Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States.   

Mealey KL, Bentjen SA, Waiting DK.  Department of Veterinary Clinical Sciences, Washington State University, Pullman 99164-6610, USA.

OBJECTIVE: To determine the frequency of the MDR1 gene mutation (polymorphism) associated with ivermectin sensitivity in a sample population of Collies in Washington and Idaho. ANIMALS: 40 healthy client-owned Collies. PROCEDURE: A blood sample (8 ml) was collected from each dog and used for RNA extraction. Reverse transcriptase was used to generate MDR1 cDNA. Polymerase chain reaction (PCR) primers were designed to amplify a 1,061-base pair region of the MDR1 gene. The PCR products were sequenced to determine whether the Collies had 0, 1, or 2 mutant alleles. Pedigrees of some dogs were available for analysis to determine relatedness of affected dogs. RESULTS: Of the 40 Collies, 9 (22%) were homozygous for the normal allele (normal), 17 (42%) were heterozygous (carrier), and 14 (35%) were homozygous for the mutant allele (affected). Pedigree analysis revealed that some, but not all, affected dogs were related to each other within the 4 most recent generations. CONCLUSIONS AND CLINICAL RELEVANCE: A high percentage of a sample population of Collies in Washington and Idaho are affected or carriers of the mutant MDR1 allele associated with ivermectin sensitivity. A similar frequency of this mutation may be detected in dogs from other geographic areas. Pharmacologic treatment with ivermectin, loperamide, vincristine, and other drugs that are substrates of P-glycoprotein, the MDR1 gene product, may result in neurologic toxicosis in a high percentage of Collies. J Am Vet Med Assoc. 1999 Dec 15;215(12):1813-7, 1806.
Respiratory failure attributable to moxidectin intoxication in a dog.
Beal MW, Poppenga RH, Birdsall WJ, Hughes D.  Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104-6010, USA.

A 5-month-old 22-kg (48.4-lb) sexually intact male Collie was examined after ingesting a moxidectin-containing deworming medication. The dog was comatose and had respiratory arrest after progressively worsening lethargy, ataxia, and seizures. Exposure was confirmed by isolation of moxidectin from a biopsy specimen of adipose tissue, using liquid chromatography-mass spectroscopy methods. Treatment included use of intermittent positive-pressure ventilation, activated charcoal and cathartic administered enterally, nutrients administered via nasogastric tube, and intensive supportive care. The dog was weaned from a ventilator on day 6 after ingestion and was discharged on day 10. The dog was considered clinically normal during examination 24 days after ingestion. On the basis of the dog reported here and toxicologic data provided by the manufacturer of the deworming product, some Collies may have increased susceptibility to products containing high doses of moxidectin. American Journal of Veterinary Research 52:1170-1177. Assessment of Toxicosis Induced by High-Dose Administration of Milbemycin Oxime in Collies. Tranquilli, W. J., A. J. Paul, and K. S. Todd. 1991.

Fifteen Collies, previously having mild reactions to ivermectin challenge (120-mu-g/kg of body weight; 20 times the recommended dosage level), were studied to evaluate the effects of milbemycin oxime administration at 5 and 10 mg/kg (10 and 20 times the manufacturer's recommended dosage). Five replicates, comprising 3 dogs each, were formed on the basis of body weight. Within replicates, each dog was randomly allocated to treatment with 5 or 10 mg of milbemycin/kg or served as a untreated control. Dogs were examined repeatedly for signs of toxicosis for 4 days after treatment and daily thereafter. Two of 5 dogs treated at 5 mg/kg (10x) developed signs of mild depression on the day of treatment, but were normal 24 hours after treatment. All 5 dogs treated at 10 mg/kg (20x) developed signs of mild depression and ataxia by 6 hours. Signs persisted for 24 hours in 3 dogs. Two of these dogs also had mydriasis, whereas 3 salivated excessively. All dogs recovered completely by day 2 after treatment. The results of this study demonstrated that Collies sensitive to the effects of 120-mu-g of ivermectin (20x)/kg show similar sensitivity to the effects of milbemycin oxine administered at 10 mg/kg (20x). We conclude that ivermectin and milbemycin commercial formulations have similar margins of safety and that milbemycin toxicosis appears to be dose-dependent in Collies with a demonstrated sensitivity to ivermectin.  Dog and Kennel Magazine.  Ivermectin and the macrocyclic lactones.  Salvation or curse?  Leslie Crane Rugg.  Click here to view article, reprinted with permission.

Selected References:

MDR1 MDR1

MDR1 MDR1

MDR1 mdr1-1Δ

mdr1-1Δ mdr1-1Δ