Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity.
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.
Mealey
Katrina L
KL
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA.
Northrup
Nicole C
NC
Bentjen
Steven A
SA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000969:Antinematodal Agents / Q000009:adverse effects / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D019450:Genes, MDR; D007559:Ivermectin / Q000009:adverse effects / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy / Q000662:veterinary; D010375:Pedigree; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000969:Antinematodal Agents; D000970:Antineoplastic Agents; D007559:Ivermectin