Pharmaceutical Research

, Volume 16, Issue 7, pp 1035–1040 | Cite as

Inhibition of Intestinal Metabolism of the Antiviral Ester Prodrug bis(POC)-PMPA by Nature-Identical Fruit Extracts as a Strategy to Enhance Its Oral Absorption: An In Vitro Study

  • Jan Van Gelder
  • Pieter Annaert
  • Lieve Naesens
  • Erik De Clercq
  • Guy Van den Mooter
  • Renaat Kinget
  • Patrick Augustijns
Article

Abstract

Purpose. To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensitive prodrugs.

Methods. Inhibition of esterase-mediated degradation by nature-identical fruit extracts was evaluated using 1) p-nitrophenylacetate (model substrate for esterase-activity) in rat intestinal homogenates and 2) bis(isopropyloxycarbonyloxymethyl)-(R)-9-[(2-phosphonomethoxy) propyl]adenine [bis(POC)-PMPA] (esterase-sensitive prodrug of the antiviral agent PMPA) in Caco-2 cell homogenates and in intestinal homogenates from rat, pig and man. Subsequently, transport of the ester prodrug was studied across Caco-2 monolayers in the presence or absence of fruit extracts.

Results. In homogenates from rat ileum, the esterase activity could be reduced significantly by the inclusion of fruit extracts (1%): the initial enzymatic degradation of p-nitrophenylacetate was inhibited by 77% (strawberry), 16% (passion fruit) and 57% (banana). A similar inhibition of bis(POC)-PMPA metabolism by fruit extracts was observed in intestinal homogenates from several species and in homogenates from Caco-2 cells. Transport of total PMPA across Caco-2 monolayers was enhanced 3-fold by co-incubation with strawberry extract (1%). The fraction of intact prodrug appearing in the acceptor compartment increased from virtually zero to 67%.

Conclusions. The results suggest that co-incubation with nature-identical fruit extracts might be useful as a strategy to enhance the transepithelial transport of esterase-sensitive prodrugs through inhibition of intracellular metabolism of the prodrug.

fruit extracts esterase inhibition bis(POC)-PMPA ester prodrug Caco-2 cells absorption enhancer 

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Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Jan Van Gelder
    • 1
  • Pieter Annaert
    • 1
  • Lieve Naesens
    • 2
  • Erik De Clercq
    • 2
  • Guy Van den Mooter
    • 1
  • Renaat Kinget
    • 1
  • Patrick Augustijns
    • 1
  1. 1.Laboratorium voor Farmacotechnologie en Biofarmacie, Campus GasthuisbergO&NKULeuvenBelgium
  2. 2.Rega Institute for Medical ResearchKULeuvenBelgium

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