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Research ArticleArticle

Effect of Coadministration of Single and Multiple Doses of Rifampicin on the Pharmacokinetics of Fexofenadine Enantiomers in Healthy Subjects

Hiroyuki Kusuhara, Masatomo Miura, Norio Yasui-Furukori, Kenta Yoshida, Yumiko Akamine, Miyu Yokochi, Shinya Fukizawa, Kazuaki Ikejiri, Kayoko Kanamitsu, Tsukasa Uno and Yuichi Sugiyama
Drug Metabolism and Disposition January 2013, 41 (1) 206-213; DOI: https://doi.org/10.1124/dmd.112.048330
Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Masatomo Miura
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Norio Yasui-Furukori
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Kenta Yoshida
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Yumiko Akamine
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Miyu Yokochi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Shinya Fukizawa
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Kazuaki Ikejiri
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Kayoko Kanamitsu
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Tsukasa Uno
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Yuichi Sugiyama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., K.Y., M.Y., S.F., K.I., K.K.); Department of Pharmacy, Akita University Hospital, Akita, Japan (M.M.); Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan (N.Y.-F.); Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan (Y.A., T.U.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Abstract

The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CLtot/F) and renal clearance (CLr) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CLtot/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CLtot/F of fexofenadine enantiomers, whereas the stereoselectivity in the CLr persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)–mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.

Footnotes

  • This study was supported partly by a Grant-in-Aid for Scientific Research (S) [Grant 24229002] and a Grant-in-Aid for Scientific Research (B) [Grant 23390034] from the Japan Society for the Promotion of Science, Japan, and partly by a Grant-in-Aid for Scientific Research on Innovative Areas HD-Physiology [Grant 23136101] from the Ministry of Education, Science, and Culture of Japan.

  • dx.doi.org/10.1124/dmd.112.048330.

  • Received August 1, 2012.
  • Accepted October 26, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
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1 Jan 2013
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Research ArticleArticle

Effect of Rifampicin on Fexofenadine Pharmacokinetics

Hiroyuki Kusuhara, Masatomo Miura, Norio Yasui-Furukori, Kenta Yoshida, Yumiko Akamine, Miyu Yokochi, Shinya Fukizawa, Kazuaki Ikejiri, Kayoko Kanamitsu, Tsukasa Uno and Yuichi Sugiyama
Drug Metabolism and Disposition January 1, 2013, 41 (1) 206-213; DOI: https://doi.org/10.1124/dmd.112.048330

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Research ArticleArticle

Effect of Rifampicin on Fexofenadine Pharmacokinetics

Hiroyuki Kusuhara, Masatomo Miura, Norio Yasui-Furukori, Kenta Yoshida, Yumiko Akamine, Miyu Yokochi, Shinya Fukizawa, Kazuaki Ikejiri, Kayoko Kanamitsu, Tsukasa Uno and Yuichi Sugiyama
Drug Metabolism and Disposition January 1, 2013, 41 (1) 206-213; DOI: https://doi.org/10.1124/dmd.112.048330
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