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NLM AIDSLINE
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.
Van Gelder J; Annaert P; Naesens L; De Clercq E; Van den Mooter G;
December 30, 1999
Pharm Res. 1999 Jul;16(7):1035-40. Unique Identifier : AIDSLINE

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.

JOURNAL ARTICLE Absorption Adenine/*ANALOGS & DERIVATIVES/ANTAGONISTS & INHIB/METABOLISM/ PHARMACOKINETICS Animal Anti-HIV Agents/*METABOLISM/PHARMACOKINETICS Biological Transport Caco-2 Cells Epithelial Cells/DRUG EFFECTS/METABOLISM Flavoring Agents/PHARMACOLOGY Fruit/*CHEMISTRY Human In Vitro Intestinal Absorption Intestinal Mucosa/DRUG EFFECTS/*METABOLISM Mouth Mucosa/DRUG EFFECTS/*METABOLISM Organophosphorus Compounds/*ANTAGONISTS & INHIB/*METABOLISM/ PHARMACOKINETICS Plant Extracts/PHARMACOLOGY Prodrugs/*METABOLISM/PHARMACOKINETICS Rats Support, Non-U.S. Gov't Swine

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