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Journal of Pharmacology And Experimental Therapeutics Fast Forward

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  • Journal of Pharmacology And Experimental Therapeutics Fast Forward

    Journal of Pharmacology And Experimental Therapeutics Fast Forward
    ANTI-INFLUENZA VIRAL PRODRUG OSELTAMIVIR IS ACTIVATED BY CARBOXYLESTERASE HCE1 AND THE ACTIVATION IS INHIBITED BY ANTI-PLATELET AGENT CLOPIDOGREL

    <nobr>Deshi Shi <sup>1</sup>,</nobr> <nobr>Jian Yang <sup>1</sup>,</nobr> <nobr>Dongfang Yang <sup>1</sup>,</nobr> <nobr>Edward L LeCluyse <sup>2</sup>,</nobr> <nobr>Chris Black <sup>2</sup>,</nobr> <nobr>Li You <sup>1</sup>,</nobr> <nobr>Fatemeh Akhlaghi <sup>1</sup>,</nobr> <nobr>Bingfang Yan <sup>1</sup><sup>*</sup></nobr>

    University of Rhode Island <sup>2</sup> CellDirect



    Abstract

    Oseltamivir is the main medicine recommended by the World Health<sup> </sup>Organization in anticipation of next influenza pandemic. This<sup> </sup>anti-influenza viral agent is an ester prodrug and the anti-viral<sup> </sup>activity is achieved by its hydrolytic metabolite: oseltamivir<sup> </sup>carboxylate.

    In this study, we report that the hydrolytic activation<sup> </sup>is catalyzed by carboxylesterase HCE1. Liver microsomes rapidly<sup> </sup>hydrolyzed oseltamivir, but no hydrolysis was detected with<sup> </sup>intestinal microsomes or plasma.

    The overall rate of the hydrolysis<sup> </sup>varied among individual liver samples and was correlated well<sup> </sup>with the level of HCE1. Recombinant HCE1 but not HCE2 hydrolyzed<sup> </sup>this prodrug and produced similar kinetic parameters as the<sup> </sup>liver microsomes. Several HCE1 natural variants differed from<sup> </sup>the wild type enzyme on the hydrolysis of oseltamivir.

    In the<sup> </sup>presence of anti-platelet agent clopidogrel, the hydrolysis<sup> </sup>of oseltamivir was inhibited by as much as 90% when the equal<sup> </sup>concentration was assayed.

    Given the fact that hydrolysis of<sup> </sup>oseltamivir is required for its therapeutic activity, concurrent<sup> </sup>use of both drugs would inhibit the activation of oseltamivir,<sup> </sup>thus making this anti-viral agent therapeutically inactive.<sup> </sup>

    This is epidemiologically of significance, because people who<sup> </sup>receive oseltamivir and clopidogrel simultaneously may maintain<sup> </sup>susceptibility to influenza infection or a source of spreading<sup> </sup>influenza virus if already infected.


    Last edited by Snowy Owl; November 7, 2006, 07:05 PM.

  • #2
    Re: Journal of Pharmacology And Experimental Therapeutics Fast Forward

    This is of premium importance. ( bump! )

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    • #3
      Re: Journal of Pharmacology And Experimental Therapeutics Fast Forward

      Snowy, do you have a link or date for this? I want to share it with the pharmacists at work...I'd need the reference for them.

      Thanks!
      Upon this gifted age, in its dark hour,
      Rains from the sky a meteoric shower
      Of facts....They lie unquestioned, uncombined.
      Wisdom enough to leech us of our ill
      Is daily spun, but there exists no loom
      To weave it into fabric..
      Edna St. Vincent Millay "Huntsman, What Quarry"
      All my posts to this forum are for fair use and educational purposes only.

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      • #4
        Clopidogrel

        Description of:

        http://www.nlm.nih.gov/medlineplus/d...di/203403.html

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        • #5
          Re: Journal of Pharmacology And Experimental Therapeutics Fast Forward

          Sorry LMonty my forgoy.

          I have inserted the linl in the original post.

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