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Multi-drug resistance gene (MDR1): overview

icanis

Synonym(s): Ivermectin toxicity / ABCB1


Introduction

  • A problem with the multi-drug resistance gene (MDR-1, also known as ABCB1) was first noticed when ivermectin administration caused severe neurological signs, seizures and death in Rough Collies Collie - Rough Ivermectin toxicity.
  • The multi-drug resistance gene encodes a cellular efflux pump called P-glycoprotein. This pump is found in a variety of tissues and is an essential part of the blood brain barrier, preventing drugs and toxins from accumulating in high concentrations. It is also expressed on biliary canalicular cells where it pumps substrate drugs into bile, enhancing excretion from the body.
  • If the MDR-1 gene mutation is present then P-glycoprotein function is affected. Dogs with one copy of the mutation (heterozygotes) have an intermediate phenotype; dogs with two copies of the MDR1 mutation (homozygotes) experience extreme drug sensitivity when exposed to P-glycoprotein substrate drugs.
  • Since its discovery in Rough Collies the MDR-1 mutation has been found in a several related herding breeds and their crosses (see affected breed section below). Further investigations revealed that many drugs are transported by P-glycoprotein and these include anti-arrhythmic, analgesics, antibiotics, chemotherapy agents, and the antidiarrheal drug loperamide Loperamide.

Drugs that are P-glycoprotein substrates and have been documented to cause toxicity

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Affected Breeds

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Diagnosis

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Therapeutic considerations

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Breeding considerations

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Tappin S W, Goodfellow M R, Peters I R et al (2012) Frequency of the mutant MDR1 allele in dogs in the United Kingdom. Vet Rec 171 (3), 72 PubMed.
  • Gramer I, Leidolf R, Döring B et al (2011) Breed distribution of the nt230(del4) MDR1 mutation in dogs. Vet J 189 (1), 67-71 PubMed.
  • Martinez M, Modric S, Sharkey M et al (2008) The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. J Vet Pharmacol Therap 31 (4), 285-300 PubMed.
  • Henik R A, Kellum H B, Bentjen S A et al (2006) Digoxin and mexiletine sensitivity in a Collie with the MDR1 mutationJVIM 20 (2), 415-417 PubMed.
  • Neff M W, Robertson K R, Wong A K et al (2004) Breed distribution and history of canine mdr1-1delta a pharmacogenetics mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci U S A 101 (32), 11725-11730 PubMed.

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