USE OF MUCCOSAL CELL CARRIERS/EYZYMES IN ORAL ABSORPTION

大多数药物在剂量的一小部分被被动口服吸收。 吸收取决于剂量、溶解度、pKa、分配系数等。 然而，作为氨基酸类似物或小分子氨基酸的药物或前药 多肽可以利用肠道粘膜细胞吸收。 负责蛋白质消化和吸收的酶/载体。近期 研究表明，甲基多巴和几种β-内酰胺类抗生素 以非被动(载体介导)的方式吸收。 拟议研究的第一个组成部分是调查口腔 三肽类似物β-内酰胺类抗生素的吸收。 对于β-内酰胺类抗生素，被动通透性和载体 将确定参数并吸收结构/性能 推断出的关系。实验方法和数据分析是基于 一种分析肠道血流灌注研究的新方法 Michaelis-Menten和被动膜渗透性组分 运输。拟议研究的第二个组成部分是开发一种 提高前药吸收分数剂量的前药策略 甲基多巴。该策略基于已知的GI管腔、笔刷边界和 胞浆酶专一性和二/三肽载体系统。十七 选定的多肽将被合成并在大鼠模型中进行评估。这个 实验系统将使用两种肠道灌流技术 通透性参数和门静脉插管的测定 测量回到母体药物的生物转化率。竞争性抑制物研究 将在两项研究中被用来证实非被动/载体 组件。 虽然拟议的研究使用了两种不同的治疗类别，但 这些药物的口服给药有一个共同的机制基础。《长河》 提出研究的术语目标是开发一种系统的 对胃肠道粘膜细胞酶及其载体的认识 在蛋白质消化/吸收中起作用，并利用这一知识 改善氨基酸类似物或小分子药物的输送 多肽。

Most drugs are passively absorbed orally with the fraction of the dose absorbed depending on dose, solubility, pKa, partition coefficient, etc. However, drugs or prodrugs which are analogs of amino acids or small peptides may be absorbed utilizing the intestinal mucosal cell enzymes/carriers responsible for protein digestion and absorption. Recent studies suggest that Alpha-methyldopa and several Beta-lactam antibiotics are absorbed in a nonpassive (carrier mediated) manner. The first component of the proposed research is to investigate the oral absorption of Beta-lactam antibiotics which are analogs of tripeptides. For the Beta-lactam antibiotics, passive permeability and carrier parameters will be determined and structure/property absorption relationships inferred. The experimental method and data analysis is based on a new method of analyzing intestinal perfusion studies with both Michaelis-Menten and passive permeability components to membrane transport. The second component of the proposed research is to develop a prodrug strategy for improving the fraction dose absorbed of Alpha-methyldopa. The strategy based on known GI luminal, brush border and cytosol enzyme specificity and the di/tripeptide carrier system. Seventeen selected peptides will be synthesized and evaluated in the rat model. The experimental system will employ both intestinal perfusions for determination of permeability parameters and portal vein cannulation to measure bioconversion back to parent drug. Competitive inhibitor studies will be employed in both studies to substantiate the nonpassive/carrier component. While the proposed studies utilize two different therapeutic classes, the oral delivery of these agents have a common mechanistic basis. The long term object of the proposed research is to develop a systematic understanding of the gastrointestinal mucosal cell enzymes and carriers that function in protein digestion/absorption and to use this knowledge to improve the delivery of drugs which are analogs of amino acids or small peptides.