title: Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene.
abstract: OBJECTIVE
  To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708, USA.
authors.forename: Krystyna L
authors.initials: KL
authors.lastname: Orzechowski
authors.forename: Marla D
authors.initials: MD
authors.lastname: Swain
authors.forename: Martin G
authors.initials: MG
authors.lastname: Robl
authors.forename: Constante A
authors.initials: CA
authors.lastname: Tinaza
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Swaim
authors.forename: Yolanda L
authors.initials: YL
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Myers
authors.forename: Haile F
authors.initials: HF
authors.lastname: Yancy
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000871:Anthelmintics / Q000633:toxicity*; D001259:Ataxia / Q000503:physiopathology / Q000662:veterinary; D004283:Dog Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004285:Dogs; D016368:Frameshift Mutation; D005838:Genotype; D007279:Injections, Subcutaneous / Q000662:veterinary; D007559:Ivermectin / Q000633:toxicity*; D053609:Lethargy / Q000503:physiopathology / Q000662:veterinary; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D014202:Tremor / Q000503:physiopathology / Q000662:veterinary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D012313:RNA; D007559:Ivermectin