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Research ArticleArticle

The Anti-Influenza Drug Oseltamivir Exhibits Low Potential to Induce Pharmacokinetic Drug Interactions via Renal Secretion—Correlation of in Vivo and in Vitro Studies

George Hill, Tomas Cihlar, Charles Oo, Edmund S. Ho, Ken Prior, Hugh Wiltshire, Jo Barrett, Baulian Liu and Penny Ward
Drug Metabolism and Disposition January 2002, 30 (1) 13-19; DOI: https://doi.org/10.1124/dmd.30.1.13
George Hill
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Tomas Cihlar
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Charles Oo
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Edmund S. Ho
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Ken Prior
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Hugh Wiltshire
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Jo Barrett
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Baulian Liu
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Penny Ward
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Abstract

Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport ofp-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.

Footnotes

  • The studies were sponsored by Roche Pharmaceutical and Gilead Sciences.

  • Abbreviations used are::
    Ro 64-0802
    [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate
    OCT
    organic cation transport
    OAT
    organic anion transporter
    hOAT
    human renal organic anion transporter
    OATP
    organic anion transporter polypeptide
    PAH
    p-aminohippuric acid
    AUC
    area under the curve
    CHOhOAT
    Chinese hamster ovary cells transfected to express functional hOAT1
    CHOpIRES
    control cells transfected with the pIRESneo expression vector
    CLR
    renal clearance
    • Received June 6, 2001.
    • Accepted September 20, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (1)
Drug Metabolism and Disposition
Vol. 30, Issue 1
1 Jan 2002
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Research ArticleArticle

The Anti-Influenza Drug Oseltamivir Exhibits Low Potential to Induce Pharmacokinetic Drug Interactions via Renal Secretion—Correlation of in Vivo and in Vitro Studies

George Hill, Tomas Cihlar, Charles Oo, Edmund S. Ho, Ken Prior, Hugh Wiltshire, Jo Barrett, Baulian Liu and Penny Ward
Drug Metabolism and Disposition January 1, 2002, 30 (1) 13-19; DOI: https://doi.org/10.1124/dmd.30.1.13

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Research ArticleArticle

The Anti-Influenza Drug Oseltamivir Exhibits Low Potential to Induce Pharmacokinetic Drug Interactions via Renal Secretion—Correlation of in Vivo and in Vitro Studies

George Hill, Tomas Cihlar, Charles Oo, Edmund S. Ho, Ken Prior, Hugh Wiltshire, Jo Barrett, Baulian Liu and Penny Ward
Drug Metabolism and Disposition January 1, 2002, 30 (1) 13-19; DOI: https://doi.org/10.1124/dmd.30.1.13
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