Scientific Publications by FDA Staff

Res Vet Sci 2013 Jun;94(3):656-61

P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.

Swain MD, Orzechowski KL, Swaim HL, Jones YL, Robl MG, Tinaza CA, Myers MJ, Jhingory MV, Buckely LE, Lancaster VA, Yancy HF

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 (ABCB1-1Delta) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Delta 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 ABCB1-1Delta 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.