Ivermectin and Multi Drug Sensitivity

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Ivermectin and multi-drug sensitivity is an autosomal-recessive genetic disease characterized by reactions to various pharmaceuticals.

This disease has been reported in the Australian Shepherd, Whippet, Shetland Sheepdog, Old English Sheepdog, Greater Swiss Mountain Dog, Border Collie, and various rough and smooth Collie breeds[1][2] and is associated with a defect in the ATP-binding cassette transporter B1 (ABCB1 gene; formerly MDR1 gene) that results in a lack of functional P-glycoprotein, which leads to accumulation of the drugs in the central nervous system and a higher risk of adverse effects when exposed[3].

This gene encodes a protein, P-glycoprotein that is an integral component of the blood-brain barrier as an efflux pump for xenobiotics crucial in limiting drug uptake into the central nervous system[4]. Dogs with the mutant gene cannot pump some drugs out of the brain as a normal dog would, which may result in abnormal neurologic signs.

This genetic mutations results in a predisposition to allergic reactions to a wide-range of ivermectin-based and other drugs.

Dogs that are homozygous for the deletion mutation display the ivermectin-sensitive phenotype, while those that are homozygous normal or heterozygous do not display increased sensitivity to ivermectin.

Drugs which are commonly reported in MRD-1 affected dogs include:

Clinically affected dogs present with acute anorexia, fever, ataxia, seizures and death following application of various drugs, particularly macrocyclic lactones.

A tentative diagnosis can be made on clinical history of recently applied pharmaceutical drugs, but definitive diagnosis requires PCR or DNA testing[7]. This test is most commonly used for Ivermectin sensitivity but many other drugs are included.

A differential diagnosis would include ivermectin toxicosis and other causes of seizures such as Cryptococcus spp.

Use of these drugs in ivermectin sensitive patients does not inevitably result in neurological symptoms[8] and veterinarians are recommended to reduce the dosage by 25% in MDR1 carriers and by 30 - 50% in MDR1 affected dogs[9].

References

  1. Gramer I et al (2011) Breed distribution of the nt230(del4) MDR1 mutation in dogs. Vet J 189(1):67-71
  2. Mealey KL et al (2001) Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11(8):727-733
  3. Merola VM & Eubig PA (2012) Toxicology of avermectins and milbemycins (macrocylic lactones) and the role of P-glycoprotein in dogs and cats. Vet Clin North Am Small Anim Pract 42(2):313-333
  4. Mizukami K et al (2012) Rapid genotyping assays for the 4-base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs. J Vet Diagn Invest 24(1):127-134
  5. Burkhardt W et al (2012) Milbemycinoxime intoxication in a Miniature Australian Shepherd dog. Schweiz Arch Tierheilkd 154(8):345-348
  6. Gustafson DL & Thamm DH (2010) Pharmacokinetic modeling of doxorubicin pharmacokinetics in dogs deficient in ABCB1 drug transporters. J Vet Intern Med 24(3):579-586
  7. Klintzsch S et al (2010) Detection of the nt230[del4] MDR1 mutation in dogs by a fluorogenic 5' nuclease TaqMan allelic discrimination method. Vet J 185(3):272-277
  8. Sherman JG et al (2010) Evaluation of the safety of spinosad and milbemycin 5-oxime orally administered to Collies with the MDR1 gene mutation. Am J Vet Res 71(1):115-119
  9. Geyer J & Janko C (2012) Treatment of MDR1 mutant dogs with macrocyclic lactones. Curr Pharm Biotechnol 13(6):969-986