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Drug Metabolism & Disposition

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Research ArticleArticle

P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION

Harunobu Tahara, Hiroyuki Kusuhara, Eiichi Fuse and Yuichi Sugiyama
Drug Metabolism and Disposition July 2005, 33 (7) 963-968; DOI: https://doi.org/10.1124/dmd.105.004192
Harunobu Tahara
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Hiroyuki Kusuhara
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Eiichi Fuse
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Yuichi Sugiyama
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Abstract

Fexofenadine is a selective, nonsedating H1-receptor antagonist approved for symptoms of allergic conditions, which is mainly excreted into feces via biliary excretion. The purpose of this study is to investigate its pharmacokinetics in mice and rats to determine the role of P-glycoprotein (P-gp) in its biliary excretion. In mice, biliary excretion clearance (17 ml/min/kg) accounted for almost 60% of the total body clearance (30 ml/min/kg). Comparing the pharmacokinetics after intravenous and oral administration indicated that the bioavailability of fexofenadine was at most 2% in mice. Knockout of Mdr1a/1b P-gp did not affect the biliary excretion clearance with regard to both plasma and liver concentrations, whereas the absence of P-gp caused a 6-fold increase in the plasma concentration after oral administration. In addition, the steady-state brain-to-plasma concentration ratio of fexofenadine was approximately 3-fold higher in Mdr1a/1b P-gp knockout mice than in wild-type mice. Together, these results show that P-glycoprotein plays an important role in efflux transport in the brain and small intestine but only a limited role in biliary excretion in mice. In addition, there was no difference in the biliary excretion between normal and hereditarily multidrug resistance-associated protein 2 (Mrp2)-deficient mutant rats (Eisai hyperbilirubinemic rats) and between wild-type and breast cancer resistance protein (Bcrp) knockout mice. These results suggest that the biliary excretion of fexofenadine is mediated by unknown transporters distinct from P-gp, Mrp2, and Bcrp.

Footnotes

  • This work was supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare for the Research on Advanced Medical Technology.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.004192.

  • ABBREVIATIONS: P-gp, P-glycoprotein; MDR/mdr, multidrug resistance (resistant); OATP, anion transporting polypeptide; ABC, ATP-binding cassette; Mrp2, multidrug resistance-associated protein 2; BCRP/Bcrp, breast cancer resistance protein; EHBR, Eisai hyperbilirubinemic rat; SDR, Sprague-Dawley rat; AUC0-inf, area under the plasma concentration-time curve from time 0 to infinity; I.S., internal standard; LC/MS, liquid chromatography/mass spectrometry; Z-335, [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate; BBB, blood-brain barrier.

    • Received February 11, 2005.
    • Accepted March 31, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (7)
Drug Metabolism and Disposition
Vol. 33, Issue 7
1 Jul 2005
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P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION
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Research ArticleArticle

P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION

Harunobu Tahara, Hiroyuki Kusuhara, Eiichi Fuse and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2005, 33 (7) 963-968; DOI: https://doi.org/10.1124/dmd.105.004192

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Research ArticleArticle

P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION

Harunobu Tahara, Hiroyuki Kusuhara, Eiichi Fuse and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2005, 33 (7) 963-968; DOI: https://doi.org/10.1124/dmd.105.004192
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