Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media

Journal of Controlled Release : Official Journal of the Controlled Release Society
Carsten Uhd NielsenBente Steffansen

Abstract

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in aqueous solution at pH 5.5 to 10, the release of the model drug seems to be controlled by a specific base-catalyzed hydrolysis, indicating that the compounds may remain relatively stable in the upper small intestinal lumen with a pH of approximately 6.0, but still release the model drug at the intercellular and blood pH of approximately 7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide prodrug principle is a promising drug delivery concept. However, the physico-chemical properties such as electronegativity, solubility, and log P of the drug molecule may also have an influence on the potential of these kinds of prodrugs. The purpose of the present study is to investigate whether the model drug electronegativity, estimated as Taft substitution parameter (sigma*) may influence the acid, water or ...Continue Reading

References

Sep 1, 1994·Journal of Pharmaceutical Sciences·J S KimD Fleisher
Mar 11, 1999·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·B SteffansenH Lennernäs
Jul 29, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·E I LepistB Steffansen

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Citations

Sep 5, 2001·Journal of Controlled Release : Official Journal of the Controlled Release Society·C U NielsenB Steffansen
Jan 16, 2003·Journal of Controlled Release : Official Journal of the Controlled Release Society·Anne Engelbrecht ThomsenBente Steffansen
Oct 4, 2002·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Hideki OkunishiEiichi Kakizoe
Jan 9, 2009·Bioorganic & Medicinal Chemistry·Mi Kyoung KimYouhoon Chong
May 19, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephanie HallerSara Belli
Oct 10, 2019·Mini Reviews in Medicinal Chemistry·Alexey V DobrydnevMaria V Popova
Dec 15, 2010·American Journal of Therapeutics·Congrong LinVasant Ranade
Feb 14, 2002·Chemical Reviews·A Sood, R Panchagnula
Feb 16, 2011·Journal of Medicinal Chemistry·Masayuki NinomiyaKunitomo Watanabe

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