Exploitation of the Intestinal Oligopeptide Transporter to Enhance Drug Absorption

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Abstract
Studies of the mechanisms involved in the transport of di- and tri-peptides by the intestinal oligopeptide transporter suggest a process which involves proton-dependent uptake at the apical cell membrane of the enterocytes with subsequent exit of intact di- or tri-peptides across the basolateral membrane or, alternatively, intracellular hydrolysis and exit of component amino acids across the basolateral membrane. In the development of techniques for investigating interaction of molecules with this transporter, it was demonstrated that peptidomimetics such as β-lactam antibiotics, cephalosporins, angiotensin converting enzyme inhibitors, and renin inhibitors are taken up at the apical cell membrane of entrocytes by the oliopeptide transporter. Molecules which interact with and are taken up by the oligopeptide transporter demonstrate good oral absorption. In addition, prodrugs of α-methyldopa and phosphonoformic acid which interact with the intestinal oligopeptide transporter and which have enhanced oral absorption have been synthesized. Implicit in this approach is the assumption that uptake of molecules at the apical membrane of the enterocyte is the rate-limiting step in intestinal absorption. In this review, the model for transepithelial transport of oligopeptides by the small intestine is presented along with areas for future research and potential applications for exploitation of the oligopeptide transporter in drug delivery.