Snowy Owl
Retired in 2010, In Memoriam
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
http://jpet.aspetjournals.org/cgi/content/abstract/jpet.106.111807v1
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
http://jpet.aspetjournals.org/cgi/content/abstract/jpet.106.111807v1
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.
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.
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