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Titre du document / Document title

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

Auteur(s) / Author(s)

VAN GELDER J. (1) ; ANNAERT P. (1) ; NAESENS L. (2) ; DE CLERCQ E. (2) ; VAN DEN MOOTER G. (1) ; KINGET R. (1) ; AUGUSTIJNS P. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Laboratorium voor Farmacotechnologie en Biofarmacie, Campus Gasthuisberg, O&N, KULeuven, BELGIQUE
(2) Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, BELGIQUE

Résumé / 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.

Revue / Journal Title

Pharmaceutical research    ISSN  0724-8741   CODEN PHREEB 

Source / Source

1999, vol. 16, no7, pp. 1035-1040 (15 ref.)

Langue / Language

Anglais

Editeur / Publisher

Springer, New York, NY, ETATS-UNIS  (1984) (Revue)

Mots-clés anglais / English Keywords

Antiviral

;

Prodrug

;

Ester

;

Absorption enhancer

;

Absorption

;

Adenine derivatives

;

Cell extract

;

Fruit

;

Esterases

;

Animal

;

Human

;

Biological transport

;

Gut

;

Digestive system

;

In vitro

;

Metabolism

;

Rat

;

Tumor cell

;

Established cell line

;

Enzyme inhibitor

;

Hydrolases

;

Enzyme

;

Rodentia

;

Mammalia

;

Vertebrata

;

Mots-clés français / French Keywords

Antiviral

;

Promédicament

;

Ester

;

Promoteur absorption

;

Absorption

;

Adénine dérivé

;

Extrait cellulaire

;

Fruit

;

Esterases

;

Animal

;

Homme

;

Transport biologique

;

Intestin

;

Appareil digestif

;

In vitro

;

Métabolisme

;

Rat

;

Cellule tumorale

;

Lignée cellulaire établie

;

Inhibiteur enzyme

;

Lignée CACO2

;

Hydrolases

;

Enzyme

;

Rodentia

;

Mammalia

;

Vertebrata

;

Mots-clés espagnols / Spanish Keywords

Antiviral

;

Promedicamento

;

Ester

;

Promotor absorción

;

Absorción

;

Adenina derivado

;

Extracto celular

;

Fruto

;

Esterases

;

Animal

;

Hombre

;

Transporte biológico

;

Intestino

;

Aparato digestivo

;

In vitro

;

Metabolismo

;

Rata

;

Célula tumoral

;

Línea celular establecida

;

Inhibidor enzima

;

Hydrolases

;

Enzima

;

Rodentia

;

Mammalia

;

Vertebrata

;

Localisation / Location

INIST-CNRS, Cote INIST : 20257, 35400008615768.0080

Nº notice refdoc (ud4) : 1909666



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