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

Katrina L Mealey; Nicole C Northrup; Steven A Bentjen

doi:10.2460/javma.2003.223.1453

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Journal article

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

Katrina L Mealey, Nicole C Northrup and Steven A Bentjen

Journal of the American Veterinary Medical Association, Vol.223(10), pp.1453-1455+1434

11/15/2003

DOI: https://doi.org/10.2460/javma.2003.223.1453

Handle:

https://hdl.handle.net/2376/114920

PMID: 14627096

Abstract

ATP Binding Cassette Transporter, Subfamily B, Member 1 - toxicity

Genes, MDR

Treatment Outcome

Ivermectin - pharmacology

ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics

Antineoplastic Agents - toxicity

Lymphoma - veterinary

ATP Binding Cassette Transporter, Subfamily B, Member 1 - pharmacokinetics

Lymphoma - drug therapy

Animals

Dog Diseases - drug therapy

Pedigree

Gene Deletion

Female

Antineoplastic Agents - pharmacokinetics

Antineoplastic Agents - pharmacology

Antinematodal Agents - adverse effects

Dogs - genetics

Ivermectin - adverse effects

Antinematodal Agents - pharmacology

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.

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Title: Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity
Creators: Katrina L Mealey - Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA
Nicole C Northrup
Steven A Bentjen
Publication Details: Journal of the American Veterinary Medical Association, Vol.223(10), pp.1453-1455+1434
Academic Unit: Veterinary Clinical Sciences, Department of
Publisher: United States
Identifiers: 99900547458501842
Language: English
Resource Type: Journal article

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

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