Assessment of verdinexor as a canine P-glycoprotein substrate

by Selleckchem | Oct 20 2023

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.

Comments:

The statement you provided highlights the importance of determining the P-glycoprotein (P-gp) substrate status of antineoplastic drugs intended for veterinary patients, particularly in the context of neoplastic cells expressing P-gp and the narrow therapeutic index of antineoplastic drugs. P-gp is a membrane protein that functions as an efflux pump, actively transporting various substances out of cells, including drugs. When neoplastic cells express P-gp, they can efflux drugs that are P-gp substrates, reducing the drugs' effectiveness in treating the cancer.

Additionally, animals with P-gp dysfunction, such as dogs with ABCB1-1Δ and cats with ABCB11930_1931del TC, may experience severe adverse reactions to antineoplastic drugs that are P-gp substrates. These animals can have increased overall exposure to P-gp substrate drugs due to mechanisms such as enhanced intestinal absorption, decreased biliary clearance, and greater penetration into the central nervous system, compared to animals with normal P-gp function.

To ensure the safety of using antineoplastic drugs in canine or feline cancer patients, it is crucial to determine whether the drugs are P-gp substrates. In the case of verdinexor, a study used a cell line that overexpressed canine P-gp to assess the P-gp substrate status of the drug. Both a cytotoxicity assay and a competitive flow cytometry assay were conducted, and the results indicated that verdinexor is not a substrate for canine P-gp. This information suggests that verdinexor may be a suitable antineoplastic drug option for canine or feline cancer patients with P-gp dysfunction, as it is not susceptible to efflux by P-gp and may not cause severe adverse reactions associated with P-gp substrate drugs.