Multidrug Resistance 1

c.296_299del4

c.295_298del

Genetic Disease/Disorder

Multi-Drug Resistance Gene, (MDR) codes for a protein that is responsible for protecting the brain by transporting potentially harmful chemicals away from the brain. In certain breeds, a mutation in the MDR1 gene causes sensitivity to Ivermectin, Loperamide, and a number of other drugs. As a result of the accumulation of toxins, the dog can show neurological symptoms including: ataxia, tremors, seizures, excessive salivation, obtundation, bradycardia, mydriasis, loss of menace, loss of papillary light responses, coma and respiratory arrest. Age of onset from birth, but symptoms only noted when exposed to drugs causing sensitivity.There are many different types of drugs that have been reported to cause problems. Some drugs include: Acepromazine, Butorphanol, Cyclosporin, Digoxin, Doxorubicin, Doramectin, Emodepside, Erythromycin, Ivermectin, Loperamide (Imodium), Milbemycin, Moxidectin, Paclitaxel, Rifampin, Selamectin, Vinblastine, Vincristine. Please note this list is not exhaustive and could be subject to change.

Multidrug resistance 1 is caused by a lack of P-glycoprotein drug transporter in the blood-brain barrier, which is characterized by neurotoxicity after administration of certain drugs. A genetic test is available. Neurotoxicity following drug administration, which varies according to dose, is the main sign. Dogs may show ataxia, tremors, seizures, excessive salivation, obtundation, bradycardia, mydriasis, loss of menace, loss of papillary light responses, coma and respiratory arrest (Mealey et al., 2001). P-gp normally transports some chemotherapeutic agents (Vinca alkaloids, doxorubicin), immunosuppressants (cyclosporine, tacrolimus), macrocyclic lactone antiparasitic drugs (ivermectin, loperamide, milbemycin, selamectin, moxidectin), HIV-1 protease inhibitors, and steroid hormones. (From OMIA)

The researcher has published a list of breed/types where a population frequency has been estimated. http://vcpl.vetmed.wsu.edu/docs/librariesprovider17/default-document-library/vcplflier.pdf In addition, the research team has identified the MDR1 mutation at very low frequencies in other breeds and mixed breed dogs, including those not apparently part of a herding breed. The recommendation would be to test all affected breeds and mixed breed dogs before treating with drugs from the problem drug list. In addition, WSU VCPL offers clinical pharmacology counseling for patients, working with owners and veterinarians to provide information on appropriate dose reductions, alternate drug choices and avoidance of drug-drug interactions.

Mealey, KL., Bentjen, SA., Gay, JM., Cantor, GH. : Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727-33, 2001. Pubmed reference: 11692082.