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

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 usi ng the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for be nzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in a queous 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 com pounds may remain relatively stable in the upper small intestinal lumen wit h a pH of similar to6.0, but still release the model drug at the intercellu lar and blood pH of similar to7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide p rodrug principle is a promising drug delivery concept. However, the physico -chemical properties such as electronegativity, solubility, and log P of th e 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 (si gma*) may influence the acid, water or base catalyzed model drug release ra tes, when released from series of D-Glu-Ala and D-Asp-Ala pro-moieties. Rel ease rates were investigated in both aqueous solutions with varying pH, ion ic strength, and buffer concentrations as well as in in vitro biological me dia. The release rates of all the investigated model drug molecules followe d first-order kinetics and were dependent on buffer concentration, pH, ioni c strength, and model drug electronegativity. The electronegativity of the model drug influenced acid, water and base catalyzed release from D-Asp-Ala and D-Glu-Ala pro-moieties. The model drug was generally released faster f rom D-Asp-Ala- than from the D-Glu-Ala pro-moieties. In biological media th e release rate was also dependent on the electronegativity of the model dru g. These results demonstrate that the model drug electronegativity, estimat ed as Taft (sigma*) values, has a significant influence on the release rate of the model drug. (C) 2001 Elsevier Science B.V. All rights reserved.