MUCOSAL CELL TRANSPORTERS & ENZYMES IN DRUG DELIVERY

拟议研究的长期目标是开发一种 提高药物膜转运效率的机理探讨 药物递送。我们将重点关注胃肠道运输，但也 包括膜转运和转运体表达或以上 通过转导方法表达，例如通过载体或病毒基因 HPEPT1的传递，以提高药物的疗效。我们对分子的理解 正在以非常快的速度进化，这是因为 分子生物学、人类遗传学和生物信息学的进展。 这个拟议的项目是已经取得的进展的延续 在粘膜细胞多肽和模拟肽转运中制成 新陈代谢与粘膜细胞的分子理解 基于克隆的人质子偶联肽转运的研究 系统(HPEPT1)。这个转运体负责肠道 二肽、三肽的吸收及重要的多肽仿造物 药物包括β-内酰胺抗生素和血管紧张素转换酶抑制剂。非常 最近，我们展示了一个令人兴奋的发现，即核苷 酯类前药，如万乃洛韦和AZT的伐他酯，利用 这个传送器。本研究项目将对这一点进行扩展和开发 I)合成给药的广泛结构特异性 抗病毒和抗癌治疗药物前药，2. 结构迁移和结构水解度的测定 多种核苷和氨基酸的相互关系 二肽类似物，III)酯酶的鉴定和克隆 负责酯类前体药物水解酶和，iv)体内 人体研究确定多肽之间的相关性 载体介导的万乃洛韦的转运蛋白活性和吸收， 头孢氨苄。这些人体研究的一个独特而重要的组成部分 将进行肠道活检取样，以测量其水平 肠肽转运体(HPEPT1)和酯酶水平。 这些吸收和吸收的分子决定因素的相关性 肠道药物渗透性、PEFF值和 全身血浆水平(Cmax和AUC)将提供基本的 体内药物作用因素的分子理解 吸收和吸收变异。这将指引未来 优化药物吸收和增强作用的药物和前药设计 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.