USE OF MUCCOSAL CELL CARRIERS/EYZYMES IN ORAL ABSORPTION

粘膜细胞载体/酶在口腔吸收中的用途

• 批准号: 3292316
• 负责人: GORDON L AMIDON
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3292316
• 关键词: aminoacid; aminopeptidase; beta lactam antibiotic; cephalosporins; drug administration routes; drug design /synthesis /production; drug vehicle; gastrointestinal drug absorption; high performance liquid chromatography; hydrolysis; mathematical model; membrane permeability; pancreas enzyme; penicillins; peptidases; peptide analog; pharmacokinetics; prodrugs; proteolysis

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.

大多数药物用剂量的比例被动地吸收 取决于剂量，溶解度，PKA，分区系数等。 但是，是氨基酸类似物或小的药物或前药 使用肠粘膜细胞可以吸收肽 负责蛋白质消化和吸收的酶/载体。 最近的 研究表明，α-甲基甲基和几种β-内酰胺抗生素 以非通行（载体介导的）方式吸收。 拟议的研究的第一个组成部分是研究口头 β-内酰胺抗生素的吸收是三肽的类似物。 对于β-内酰胺抗生素，被动渗透性和载体 将确定参数并结构/属性吸收 关系推断。 实验方法和数据分析基于 关于分析肠道灌注研究的新方法 Michaelis-Menten和膜的被动渗透率成分 运输。 拟议研究的第二个组成部分是开发 前药策略，以改善吸收的分数剂量 alpha-methyldopa。 该策略基于已知的Gi Luminal，Brush Border和 细胞质酶特异性和DI/三肽载体系统。 十七 选定的肽将在大鼠模型中合成和评估。 这 实验系统将采用两种肠道灌注 确定渗透率参数和门静脉插管 测量生物转化回到家长药物。 竞争性抑制剂研究 两项研究都将用于证实非通行/载体 成分。 拟议的研究利用两个不同的治疗类别，但 这些药物的口服递送具有共同的机械基础。 长 拟议研究的术语对象是开发系统的 了解胃肠道粘膜细胞酶和载体 该功能在蛋白质消化/吸收中，并利用这些知识 改善药物的输送，即氨基酸或小的类似物 肽。