Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity

J Am Vet Med Assoc. 2003 Nov 15;223(10):1453-5, 1434. doi: 10.2460/javma.2003.223.1453.


Lymphoma was diagnosed in a 4-year-old spayed female Collie, and treatment with a combination chemotherapy protocol incorporating prednisone, L-asparaginase, vincristine, vinblastine, doxorubicin, and cyclophosphamide was initiated. The dog had signs of gastrointestinal tract toxicosis and myelosuppression after treatment with P-glycoprotein-substrate drugs (vincristine, vinblastine, and doxorubicin) even when dosages were reduced, but did not have signs of toxicosis after treatment with cyclophosphamide, a non-P-glycoprotein-substrate drug, even when administered at the full dosage. It was postulated that a deletion mutation in the canine MDR1 gene (deltaMDR1 295-298) could be responsible for the drug toxicoses in this dog. This mutation has been identified as the cause of a functional P-glycoprotein defect in Collies susceptible to the toxic effects of ivermectin, another P-glycoprotein-substrate drug. The MDR1 genotype of this dog consisted of 1 normal and 1 mutant MDR1 allele. Because P-glycoprotein contributes to renal, biliary, and intestinal excretion of P-glycoprotein-substrate drugs, it is possible that drug excretion was delayed in this patient, resulting in clinical signs of toxicosis.

Publication types

  • Case Reports

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / pharmacokinetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / toxicity*
  • Animals
  • Antinematodal Agents / adverse effects
  • Antinematodal Agents / pharmacology
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity*
  • Dog Diseases / drug therapy*
  • Dogs / genetics*
  • Female
  • Gene Deletion*
  • Genes, MDR*
  • Ivermectin / adverse effects
  • Ivermectin / pharmacology
  • Lymphoma / drug therapy
  • Lymphoma / veterinary
  • Pedigree
  • Treatment Outcome


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antinematodal Agents
  • Antineoplastic Agents
  • Ivermectin