title: P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.
abstract: Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, 8401 Muirkirk Road, Laurel, MD 20708, United States. marla.swain@fda.hhs.gov
authors.forename: M D
authors.initials: MD
authors.lastname: Swain
authors.forename: K L
authors.initials: KL
authors.lastname: Orzechowski
authors.forename: H L
authors.initials: HL
authors.lastname: Swaim
authors.forename: Y L
authors.initials: YL
authors.lastname: Jones
authors.forename: M G
authors.initials: MG
authors.lastname: Robl
authors.forename: C A
authors.initials: CA
authors.lastname: Tinaza
authors.forename: M J
authors.initials: MJ
authors.lastname: Myers
authors.forename: M V
authors.initials: MV
authors.lastname: Jhingory
authors.forename: L E
authors.initials: LE
authors.lastname: Buckely
authors.forename: V A
authors.initials: VA
authors.lastname: Lancaster
authors.forename: H F
authors.initials: HF
authors.lastname: Yancy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000502:physiology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects*; D004077:Digoxin / Q000633:toxicity*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000139:chemically induced / Q000188:drug therapy; D004285:Dogs; D004294:Domperidone / Q000633:toxicity; D005260:Female; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000633:toxicity; D018942:Macrolides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional / Q000235:genetics / Q000379:methods
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D018942:Macrolides; D004294:Domperidone; D007559:Ivermectin; D004077:Digoxin; C084101:doramectin; C027837:moxidectin