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Research ArticleArticle

Edoxaban Transport via P-Glycoprotein Is a Key Factor for the Drug’s Disposition

Tsuyoshi Mikkaichi, Yasushi Yoshigae, Hiroshi Masumoto, Tomoki Imaoka, Veronika Rozehnal, Thomas Fischer, Noriko Okudaira and Takashi Izumi
Drug Metabolism and Disposition April 2014, 42 (4) 520-528; DOI: https://doi.org/10.1124/dmd.113.054866
Tsuyoshi Mikkaichi
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.)
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Yasushi Yoshigae
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.)
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Hiroshi Masumoto
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.)
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Tomoki Imaoka
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.)
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Veronika Rozehnal
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.)
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Thomas Fischer
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.)
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Noriko Okudaira
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.)
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Takashi Izumi
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.)
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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.

Footnotes

    • Received September 13, 2013.
    • Accepted January 23, 2014.
  • This work was supported by Daiichi Sankyo, Co., Ltd. (Tokyo, Japan) and Daiichi Sankyo, Inc. (Parsippany, NJ).

  • dx.doi.org/10.1124/dmd.113.054866.

  • This work was previously presented as a poster at the following meeting: Mikkaichi T, Yoshigae Y, Masumoto H, Imaoka T, Rozehnal V, Fischer T, et al. (2012) Edoxaban transport via P-glycoprotein is a key factor for the drug disposition. 18th North American Regional ISSX Meeting; 2012 October 14–18; Dallas, TX.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

P-gp Transport Is a Key Factor for Edoxaban’s Disposition

Tsuyoshi Mikkaichi, Yasushi Yoshigae, Hiroshi Masumoto, Tomoki Imaoka, Veronika Rozehnal, Thomas Fischer, Noriko Okudaira and Takashi Izumi
Drug Metabolism and Disposition April 1, 2014, 42 (4) 520-528; DOI: https://doi.org/10.1124/dmd.113.054866

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Research ArticleArticle

P-gp Transport Is a Key Factor for Edoxaban’s Disposition

Tsuyoshi Mikkaichi, Yasushi Yoshigae, Hiroshi Masumoto, Tomoki Imaoka, Veronika Rozehnal, Thomas Fischer, Noriko Okudaira and Takashi Izumi
Drug Metabolism and Disposition April 1, 2014, 42 (4) 520-528; DOI: https://doi.org/10.1124/dmd.113.054866
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