Chadwick L West1, Katrina L Mealey. 1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA.
Abstract
OBJECTIVE: To determine whether antiepileptic drugs (AEDs) are substrates for canine P-glycoprotein (P-gp). Sample Population-OS2.4/Doxo cells (canine osteosarcoma cells induced via exposure to doxorubicin to highly express P-gp). PROCEDURES: Competitive inhibition of rhodamine 123 efflux from OS2.4/Doxo cells was used to determine whether AEDs were substrates for canine P-gp. Flow cytometry was used to quantify mean fluorescence intensity of cells treated with rhodamine alone and in combination with each experimental drug. RESULTS: Known P-gp substrate drugs ivermectin and cyclosporin A altered rhodamine efflux by 90% and 95%, respectively. Experimental drugs altered rhodamine efflux weakly (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or not at all (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide). CONCLUSIONS AND CLINICAL RELEVANCE: At clinically relevant doses, it appeared that AEDs were weak substrates (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or were not substrates (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide) for canine P-gp. Therefore, it seems unlikely that efficacy of these AEDs is affected by P-gp expression at the blood-brain barrier in dogs.
OBJECTIVE: To determine whether antiepileptic drugs (AEDs) are substrates for canineP-glycoprotein (P-gp). Sample Population-OS2.4/Doxo cells (canineosteosarcoma cells induced via exposure to doxorubicin to highly express P-gp). PROCEDURES: Competitive inhibition of rhodamine 123 efflux from OS2.4/Doxo cells was used to determine whether AEDs were substrates for canineP-gp. Flow cytometry was used to quantify mean fluorescence intensity of cells treated with rhodamine alone and in combination with each experimental drug. RESULTS: Known P-gp substrate drugs ivermectin and cyclosporin A altered rhodamine efflux by 90% and 95%, respectively. Experimental drugs altered rhodamine efflux weakly (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or not at all (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide). CONCLUSIONS AND CLINICAL RELEVANCE: At clinically relevant doses, it appeared that AEDs were weak substrates (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or were not substrates (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide) for canineP-gp. Therefore, it seems unlikely that efficacy of these AEDs is affected by P-gp expression at the blood-brain barrier in dogs.
Authors: Erwin A van Vliet; Anand M Iyer; Lucia Mesarosova; Hilal Çolakoglu; Jasper J Anink; Olaf van Tellingen; Nicholas J Maragakis; Jeremy Shefner; Ton Bunt; Eleonora Aronica Journal: J Neuropathol Exp Neurol Date: 2020-03-01 Impact factor: 3.685