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Research ArticleArticle

Role of the Intestinal Peptide Transporter PEPT1 in Oseltamivir Absorption: In Vitro and In Vivo Studies

Agnès Poirier, Sara Belli, Christoph Funk, Michael B. Otteneder, Renée Portmann, Katja Heinig, Eric Prinssen, Stanley E. Lazic, Craig R. Rayner, Gerhard Hoffmann, Thomas Singer, David E. Smith and Franz Schuler
Drug Metabolism and Disposition August 2012, 40 (8) 1556-1565; DOI: https://doi.org/10.1124/dmd.112.044990
Agnès Poirier
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Sara Belli
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Christoph Funk
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Michael B. Otteneder
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Renée Portmann
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Katja Heinig
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Eric Prinssen
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Stanley E. Lazic
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Craig R. Rayner
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Gerhard Hoffmann
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Thomas Singer
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David E. Smith
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Franz Schuler
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Abstract

It was reported that oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of oseltamivir and its active metabolite (oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of oseltamivir and oseltamivir carboxylate, after oral administration of oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, oseltamivir and oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of oseltamivir.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM035498] (to D.E.S.). D.E.S. is a consultant to F. Hoffmann-La Roche Ltd.

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

    http://dx.doi.org/10.1124/dmd.112.044990.

  • ABBREVIATIONS:

    hOAT
    human organic anion transporters
    PEPT
    peptide transporter
    CHO
    Chinese hamster ovary
    BSA
    bovine serum albumin
    PBS
    phosphate-buffered saline
    KH
    Krebs-Henseleit
    MES
    4-morpholineethanesulfonic acid
    HPLC
    high-performance liquid chromatography
    Cmax
    maximal plasma concentration
    tmax
    time to maximal concentration
    AUC
    area under the concentration-time profile
    ANOVA
    analysis of variance.

  • Received February 13, 2012.
  • Accepted May 14, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (8)
Drug Metabolism and Disposition
Vol. 40, Issue 8
1 Aug 2012
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Research ArticleArticle

ROLE OF PEPT1 IN OSELTAMIVIR ABSORPTION

Agnès Poirier, Sara Belli, Christoph Funk, Michael B. Otteneder, Renée Portmann, Katja Heinig, Eric Prinssen, Stanley E. Lazic, Craig R. Rayner, Gerhard Hoffmann, Thomas Singer, David E. Smith and Franz Schuler
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1556-1565; DOI: https://doi.org/10.1124/dmd.112.044990

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Research ArticleArticle

ROLE OF PEPT1 IN OSELTAMIVIR ABSORPTION

Agnès Poirier, Sara Belli, Christoph Funk, Michael B. Otteneder, Renée Portmann, Katja Heinig, Eric Prinssen, Stanley E. Lazic, Craig R. Rayner, Gerhard Hoffmann, Thomas Singer, David E. Smith and Franz Schuler
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1556-1565; DOI: https://doi.org/10.1124/dmd.112.044990
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