Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
J Vet Pharmacol Ther. 2023 Jul;46(4):264-267. doi: 10.1111/jvp.13123. Epub 2023 Mar 16.
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.
出于两个原因，明确兽医患者用抗肿瘤药物的 P-糖蛋白（P-gp）底物状态是一个重要特征。首先，表达 P-gp 的肿瘤细胞可以主动外排 P-gp 底物药物，从而降低其疗效。其次，抗肿瘤药物往往具有较窄的治疗指数。具有 P-gp 底物的抗肿瘤药物可能会导致 P-gp 功能障碍的动物（如 ABCB1-1Δ 突变的狗和 ABCB11930_1931del TC 突变的猫）发生严重的不良反应。与具有正常 P-gp 功能的动物相比，P-gp 功能障碍的动物由于肠道吸收增加、胆汁清除减少和中枢神经系统穿透增加等机制，对 P-gp 底物药物的总体暴露量更大。因此，在将抗肿瘤药物用于犬或猫癌症患者之前，了解其 P-gp 底物状态是一个重要的安全性考虑因素。本研究使用过表达犬 P-gp 的细胞系来评估 verdinexor 的 P-gp 底物状态。基于细胞毒性测定和竞争性流式细胞术测定，verdinexor 不是犬 P-gp 的底物。
