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 mdr1-1?.  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 mdr1-1? 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 mdr1-1? 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 mdr1-1? 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 mdr1-1? allele.

Approximately 1 in 3 or 4 Collies in the United States are homozygous for the mdr1-1? 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 mdr1-1? 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 mdr1-1? 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 mdr1-1? mutation than ivermectin. The monthly oral dose of both ivermectin and milbemycin oxime has been administered for heartworm prophylaxis to Collies homozygous for mdr1-1? 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 mdr1-1?. [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 mdr1-1? 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 mdr1-1? mutation when administered to sensitive Collies. 

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