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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.




 

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



 




Information in this article was accurate in December 30, 1999. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.