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Published on: May 10, 2015
Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated
Krystyna L Orzechowski1, Marla D Swain, Martin G Robl
1Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708, USA.
Objective:
To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies.
Animals:
14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted.
Procedures:
Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration.
Results:
After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin.
Conclusions And Clinical Relevance:
The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.
Insights
Genetically engineered mice with a mutated canine ABCB1 gene show ivermectin sensitivity, mimicking Collie drug toxicosis. This model offers an alternative to dog testing for P-glycoprotein substrate safety evaluations.
Area of Science:
- Veterinary Pharmacology
- Toxicology
- Genetics
Background:
- P-glycoprotein (P-gp) is crucial for drug efflux, and its dysfunction can lead to toxicosis.
- Ivermectin sensitivity in Collies is linked to a specific mutation in the canine ABCB1 gene, which encodes P-gp.
- Current safety testing for P-gp substrates often involves animal models that may not fully replicate canine-specific sensitivities.
Purpose of the Study:
- To develop a genetically engineered mouse model that mimics ivermectin toxicosis observed in P-glycoprotein-deficient Collies.
- To establish an alternative screening method for evaluating P-glycoprotein substrate toxicosis, reducing reliance on canine subjects.
Main Methods:
- Genetically engineered mice were created by disrupting the mouse abcb1a and abcb1b genes and inserting a mutated canine ABCB1 gene.
- Wild-type C57BL/6J mice served as controls.
- Mice received either ivermectin (10 mg/kg) or a vehicle control via subcutaneous injection and were monitored for clinical signs of toxicity for 7 hours.
Main Results:
- Genetically engineered mice exhibited severe ivermectin sensitivity, including lethargy, ataxia, and tremors.
- Wild-type control mice showed no significant adverse effects from ivermectin administration.
- The observed sensitivity in engineered mice closely mirrored clinical signs in ivermectin-sensitive Collies with the ABCB1-1Δ mutation.
Conclusions:
- The developed transgenic mouse model effectively replicates ivermectin sensitivity and toxicosis seen in specific canine populations.
- This model provides a valuable alternative for assessing the toxicity of P-glycoprotein substrates, potentially reducing the need for extensive canine safety studies.
- The model supports the development of safer drugs by offering a more targeted approach to evaluating P-gp substrate toxicosis.
