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Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene

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  • 1 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 2 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 3 Office of Applied Research and Safety Assessments, Center for Food Safety and Applied Nutrition, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 4 Office of Applied Research and Safety Assessments, Center for Food Safety and Applied Nutrition, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 5 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 6 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 7 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
  • | 8 Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.

Abstract

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.

Contributor Notes

The model of ivermectin sensitivity in genetically engineered mice was created by genOway.

Address correspondence to Dr. Yancy (haile.yancy@fda.hhs.gov).