The long-term goal of the proposed research is to develop a mechanistic approach to enhancing drug membrane transport to improve drug delivery. We will focus on gastrointestinal transport, but also include membrane transport and transporter expression or over expression via transduction methods, e.g. plasmid or viral gene hPEPT1 delivery to enhance drug efficacy. Our molecular understanding of membrane transport is evolving at a very rapid pace due to advances in molecular biology, human genetics, and bioinformatics. This proposed project is a continuation of the advances that have made in mucosal cell peptide and peptimdomimetic transport and metabolism and in the molecular understanding of mucosal cell transport based on the cloned human proton coupled peptide transport system (hPEPT1). This transporter is responsible for the intestinal absorption of di- and tri- peptides, and important peptidomimetic drugs include beta-lactum antibiotics and ACE inhibitors. Very recently we have demonstrated the exciting finding that nucleoside ester prodrugs e.g. valacyclovir and the valyl ester of AZT, utilize this transporter. This research project will extend and exploit this broad structural specificity for drug delivery through I) Synthesis of prodrugs of anti-viral and anticancer therapeutic agents, ii.) Determination of the structure transport and structure hydrolysis relationships for a diverse range of nucleosides and amino acid and di-peptide analogues, iii) Identification and cloning of the esterase enzymes responsible for ester prodrug hydrolysis and, iv.)In vivo human studies to establish the correlation between peptide transporter activity and absorption of carrier-mediated valacyclovir, cephalexin. A unique and important component of these human studies will be intestinal biopsy sampling to measure the levels of intestinal peptide transporter (hPEPT1) and, esterase enzyme levels. The correlation of these molecular determinants of absorption and systemic availability with intestinal drug permeability, Peff, and systemic plasma levels (Cmax, and AUC) will provide a fundamental molecular understanding of the factors responsible for in vivo drug absorption and absorption variation. This will guide the future design of drugs and prodrugs for optimal drug absorption and enhanced efficacy.
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