Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (T.M., Y.Y., T.Im., N.O., T.Iz.); Daiichi Sankyo Pharma Development, Edison, New Jersey, (H.M.); and Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Munich, Germany (V.R., T.F.).
Drug Metab Dispos. 2014 Apr;42(4):520-8. doi: 10.1124/dmd.113.054866. Epub 2014 Jan 23.
Edoxaban (the free base of DU-176b), an oral direct factor Xa inhibitor, is mainly excreted unchanged into urine and feces. Because active membrane transport processes such as active renal secretion, biliary excretion, and/or intestinal secretion, and the incomplete absorption of edoxaban after oral administration have been observed, the involvement of drug transporters in the disposition of edoxaban was investigated. Using a bidirectional transport assay in human colon adenocarcinoma Caco-2 cell monolayers, we observed the vectorial transport of [(14)C]edoxaban, which was completely inhibited by verapamil, a strong P-glycoprotein (P-gp) inhibitor. In an in vivo study, an increased distribution of edoxaban to the brain was observed in Mdr1a/1b knockout mice when compared with wild-type mice, indicating that edoxaban is a substrate for P-gp. However, there have been no observations of significant transport of edoxaban by renal or hepatic uptake transporters, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, or organic anion transporting polypeptide (OATP)1B1. Edoxaban exhibited no remarkable inhibition of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or P-gp up to 30 μM; therefore, the risk of clinical drug-drug interactions due to any edoxaban-related transporter inhibition seems to be negligible. Our results demonstrate that edoxaban is a substrate of P-gp but not of other major uptake transporters tested. Because metabolism is a minor contributor to the total clearance of edoxaban and strong P-gp inhibitors clearly impact edoxaban transport, the P-gp transport system is a key factor for edoxaban's disposition.
依度沙班（DU-176b 的游离碱）是一种口服直接因子 Xa 抑制剂，主要以原形经尿液和粪便排泄。由于观察到主动的膜转运过程，如主动肾分泌、胆汁排泄和/或肠分泌，以及口服依度沙班后的不完全吸收，因此研究了药物转运体在依度沙班处置中的作用。通过人结肠腺癌细胞单层 Caco-2 的双向转运试验，我们观察到 [(14)C]依度沙班的向量转运，这一转运完全被强 P-糖蛋白（P-gp）抑制剂维拉帕米所抑制。在体内研究中，与野生型小鼠相比，Mdr1a/1b 敲除小鼠中依度沙班向大脑的分布增加，表明依度沙班是 P-gp 的底物。然而，尚未观察到依度沙班通过肾或肝摄取转运体、有机阴离子转运体（OAT）1、OAT3、有机阳离子转运体（OCT）2 或有机阴离子转运多肽（OATP）1B1 进行显著转运。依度沙班对 OAT1、OAT3、OCT1、OCT2、OATP1B1、OATP1B3 或 P-gp 的抑制作用在高达 30 μM 时无明显表现；因此，由于任何与依度沙班相关的转运体抑制作用而导致的临床药物相互作用的风险似乎可以忽略不计。我们的结果表明，依度沙班是 P-gp 的底物，但不是我们测试的其他主要摄取转运体的底物。由于代谢对依度沙班总清除率的贡献较小，且强 P-gp 抑制剂明显影响依度沙班的转运，因此 P-gp 转运系统是依度沙班处置的关键因素。
