MUCOSAL CELL TRANSPORTERS & ENZYMES IN DRUG DELIVERY

拟议研究的长期目标是开发一种 增强药物膜转运以改善 药物输送 我们将重点介绍胃肠道转运，但也 包括膜转运和转运蛋白表达或其以上 通过转导方法表达，例如质粒或病毒基因 hPEPT 1递送以增强药物功效。我们对分子的理解 膜运输的发展速度非常快， 分子生物学、人类遗传学和生物信息学的进展。 这个拟议的项目是一个进步的延续， 在粘膜细胞中进行肽和肽模拟物的转运， 代谢和粘膜细胞的分子理解 基于克隆人质子偶联肽转运的转运 系统（hPEPT 1）。 这种转运蛋白负责肠道 二肽和三肽的吸收以及重要的肽模拟物 药物包括β-内酰胺类抗生素和ACE抑制剂。 非常 最近我们证明了一个令人兴奋的发现， 酯前药，例如伐昔洛韦和AZT的缬氨酰酯，利用 这个传送器。该研究项目将扩展和利用这一点， 通过I）合成用于药物递送的广泛结构特异性 抗病毒和抗癌治疗剂的前药，ii.） 结构迁移和结构水解的确定 各种核苷和氨基酸之间的关系， 二肽类似物，iii）酯酶的鉴定和克隆 负责酯前药水解的酶和，iv.）体内 人类研究，以建立肽之间的相关性， 载体介导的伐昔洛韦的转运活性和吸收， 头孢氨苄 这些人类研究的一个独特而重要的组成部分 将进行肠道活检取样，以测量 肠肽转运蛋白（hPEPT 1）和酯酶水平。 这些分子吸收决定因素的相关性， 全身利用度与肠道药物渗透性，Peff，和 全身血浆水平（Cmax和AUC）将提供基本的 对体内药物作用因子的分子理解 吸收和吸收变化。 这将指导未来 药物和前药的设计，用于最佳药物吸收和增强 功效

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.