P-glycoproteins: Their function, their absence, and the implications for heartworm prevention

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Mar 02, 2009
By dvm360.com staff
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We’ve long known that certain herding breeds, especially collies, have a sensitivity to ivermectin. The cause of this sensitivity is a deletion mutation in the ABCB1 gene (formerly known as the multidrug resistant gene, or MDR1). About two-thirds of collies have at least one mutant allele in this gene. Other breeds with this mutation are shelties, Australian shepherds, and Old English sheepdogs, although not as high of a percentage of these breeds are affected. The unmutated gene produces p-glycoprotein, which decreases exposure to administered, potentially toxic xenobiotics, including many chemotherapeutic drugs (e.g. vinblastine, doxorubicin) and macrocyclic lactones (e.g. ivermectin, selamectin, moxidectin, milbemycin). An article in Veterinary Parasitology recently reviewed the association between macrocyclic lactones and the ABCB1 gene. In essence, p-glycoprotein limits the penetration of these drugs across the blood-brain barrier, inhibits their absorption in the gastrointestinal tract, and promotes their biliary and renal excretion. In dogs with the genetic mutation, p-glycoprotein is not present, so the dogs are much more prone to toxicosis.

From a practical perspective, the author emphasized that all current heartworm preventives that contain ivermectin, selamectin, moxidectin, or milbemycin given at their recommended dosages are completely safe in dogs with the mutation. One situation that may be a risk, however, is when ivermectin formulated for cattle is used to treat a dog because it is cheaper. Protocols for these products listed on various lay Web sites would result in dosages above the toxic level in dogs with the genetic mutation. Also, some drugs can inhibit p-glycoprotein, so even in unaffected dogs, the administration of these drugs in conjunction with p-glycoprotein substrates such as macrocyclic lactones can result in toxicity. While monthly heartworm preventives formulated for dogs that contain macrocyclic lactones are safe when given at the correct dosage, other drugs, such as chemotherapeutic agents, are more of a concern for toxicosis. In these cases, genetic testing can reveal whether a dog has the mutation and whether certain drugs should be avoided to prevent toxicosis.

 

Mealey KL. Canine ABCB1 and macrocyclic lactones: heartworm prevention and pharmacogenetics. Vet Parasitol 2008;158:215-222.

Link to abstract: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TD7-4TCYCKB-9&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4a845f2b52a2d7b0e422c8c1a2930d44