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.
OBJECTIVE
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.
Van Gelder
J
J
Laboratorium voor Farmacotechnologie en Biofarmacie, O&N, KULeuven, Belgium.
Annaert
P
P
Naesens
L
L
De Clercq
E
E
Van den Mooter
G
G
Kinget
R
R
Augustijns
P
P
D000042:Absorption; D000225:Adenine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport; D018938:Caco-2 Cells; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005421:Flavoring Agents / Q000494:pharmacology; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013552:Swine; D000068698:Tenofovir
D019380:Anti-HIV Agents; D005421:Flavoring Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010936:Plant Extracts; D011355:Prodrugs; C111774:bis(isopropyloxymethylcarbonyl) 9-(2-phosphonomethoxypropyl)adenine; D000068698:Tenofovir; D000225:Adenine