Assessment of verdinexor as a canine P-glycoprotein substrate

Abstract

The P-glycoprotein (P-gp) substrate status of antineoplastic drugs intended for veterinary patients is an important characteristic to define for two reasons. First, neoplastic cells expressing P-gp can actively efflux drugs that are P-gp substrates curtailing their efficacy. Second, antineoplastic drugs tend to have a narrow therapeutic index. Antineoplastic drugs that are P-gp substrates can cause severe adverse reactions in animals with P-gp dysfunction such as dogs with ABCB1-1Δ and cats with ABCB11930_1931del TC. Animals with P-gp dysfunction experience greater overall exposure to P-gp substrate drugs due to mechanisms such as increased intestinal absorption, decreased biliary clearance and greater central nervous system penetration compared with animals with normal P-gp function. Accordingly, knowing the P-gp substrate status of antineoplastic drugs is an important safety consideration prior to use in canine or feline cancer patients. This study used a cell line overexpressing canine P-gp to assess the P-gp substrate status of verdinexor. Based on both a cytotoxicity assay and a competitive flow cytometry assay verdinexor is not a substrate for canine P-gp.