Abstract

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 [¹⁴C]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.