Author: Bente Steffansen, Danish University of Pharmaceutical Sciences.
Names and affiliation of other authors:
Oral or poster: Oral presentation
The di/tripeptide transporter hPEPT1 is located in the apical membrane of enterocytes and mediates absorption of di-/tripeptides as well as various di-/ tripeptide like drugs.
The aim of the presentation is to highlight on chemical strategies to target human peptide transporter hPEPT1 to increase oral bioavailability of low permeability drug candidates. Strategies are to design low permeability drug candidates as stabilized tripeptidic substrates or di/tripeptidic prodrugs as substrates for hPEPT1. Stabilization was done by amide bond replacement either by N-methylation or ketomethylation. Amide bond replacement seems however not to be generally applicable for increasing oral bioavailability of tripeptidic drug candidates since it tends to sometimes decrease or even abolish their affinity and/or translocation by hPEPT1 compared to corresponding /di-tripeptides. This is suggested to be due to influence on transconformation by N-methylation and thus decreased or abolished affinity to hPEPT1. Initial studies on amide bond replacement by ketomethylation seems however to be a promising strategy since model compound linked to Valψ[CH2]Asp or Aspψ[CH2]Gly is fluxed across Caco-2 cell monolayers in a PEPT1-mediated manner. These fundamental mechanistic and kinetic studies of carrier mediated transport may be of major importance for performing biosimulation of drug bioavailability