Multi-DrugResistance 1 (MDR1)is a semi-dominant mutation that causes a clinical sensitivity to anumber of common drugs (including Ivermectin) by impairing the transport ofthose drugs out of the canine brain allowing for a toxic buildup of the drugsupon administration of sufficient doses, which can lead to neurologicaldysfunction and death.
Ivermectintoxicity in Collies was first described in 1983 (Preston, 1983; Seward, 1983).Doses that are just a small part of the dose required to cause Ivermectintoxicity in other dogs, in Collies causes neural toxicity (Tranquilli et al.,1987; Paul et al., 1987).
Many investigations were done, but cause of thissusceptibility was not cleared until a mutation in MDR1 was discovered.Ivermectin sensitivity in Collies has been associated with homozygous expressionof a mutation in MDR1 gene. Thismutation (ATAG) involves four-base-pair frame-shift deletion (nt230del4 onchromosome 14, which generates a premature stop codon, thus preventingsynthesis of the complete protein product, but rather truncated, nonfunctionalprotein (Mealey et al., 2001). Two years later, this work was confirmed byother investigators (Roulet et al., 2003). MDR1 gene has also been referred toas ABCB1 based on the nomenclature of the ATP-binding cassette (ABC)transporter family (Dean, 2005). P-glycoprotein,the product of the MDR1 gene, is an important component of blood-brain barrier(Kim et al.
, 1998; Jonker et al., 1999; Fromm, 2002;). This protein is anATP-dependent drug transport pump which is expressed on the luminal membrane ofendotelial cells of the brain capillaries. It protects transportation ofdifferent subtrates, including ivermectin, from brain tissue into the capillaryvolumen, which results in lower brain concentrations of drugs that aresubstrates for P-glycoprotein. Other subtrates include doramectin, moxidectin,milbemycin oxime, loperamide, the antiemetic ondansetron, digoxin,chemotherapeutic drugs including doxorubicin, vincristine and vinblastine, aswell as many other drugs (Schinkel et al.
, 1994; Sartor et al., 2004; Geyer etal., 2005a, 2007; Mealey et al., 2008; Barbet et al., 2009). P-gp is expressedin different mammalian tissues such as the luminal membrane of proximal tubulesin the kidney, the brush border membrane of epithelial cells in the intestinaltract and the canalicular membrane of liver hepatocytes (Thiebaut et al.,1987). Oral drug bioavailability is diminished because of the apical/luminalexpression of P-glycoprotein and drugs are eliminated into urine and bile(Fromm, 2000).
Twomutant alleles of this gene are needed to display the ivermectin-sensitivephenotype and those dogs are susceptible to toxicity caused by other substratesof P-glycoprotein as well (Sartor et al., 2004). MDR1 knockout mice have provedthat lack of P-glycoprotein leads to increased accumulation of certain drugs inbrain with undesired neurologic effects (Schinkel et al., 1994).
Othersubstrates for P-glycoprotein that can cause toxicity in affected dogs arevinblastine, vincristine, doxorubicin, ondansetron and other macrolideanthelmintics.MDR1 in herdingbreeds is caused by a 4 base pair deletion (ATAG) in the ABCB1 gene onchromosome 14. Dogs that are homozygous for the deletion mutation display theivermectin-sensitive phenotype, while those that are homozygous normal orheterozygous do not display increased sensitivity to ivermectin (Washington2001).To this date, MDR1genotyping studies from different countries have shown that apart from theCollie, other dog breeds are affected by this mutation, including ShetlandSheepdog, Australian Shepherd, English Shepherd, Old English Sheepdog, WhiteShepherd, German Shepherd, Wäller, Longhaired Whippet, McNab and SilkenWindhound has been described in Collie-related breeds (Geyer et al., 2005b;Neff et al., 2004; Mealey and Meurs, 2008).