ORAL DRUG DELIVERY AND BIOAVAILABILITY

口服药物递送和生物利用度

• 批准号: 3267695
• 负责人: GORDON L AMIDON
• 金额: $ 25.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3267695
• 关键词: aniline; antihypertensive agents; antiinflammatory agents; beta antiadrenergic agent; biological models; cimetidine; computer simulation; dogs; drug administration routes; drug metabolism; fluid flow; fluorescence spectrometry; furosemide; gastrointestinal drug absorption; gastrointestinal function; high performance liquid chromatography; human subject; laboratory rat; mathematical model; membrane permeability; model design /development; perfusion; pharmacokinetics; physiology; propranolol

Studies of drug absorption have most often been performed at two very different levels: the membrane/cell/intestinal segment level and the whole animal/man level. The former focuses on membrane transport while the latter focuses on simple description of absorption. The proposed research will develop the necessary understanding and test a systematic approach to utilizing and integrating the information from these two levels. The specific aims of the proposed research are: (1) develop an approach for obtaining intestinal mucosal membrane permeabilities to obtain information more directly related to the in vivo absorption process; (2) develop and validate a physiological flow model approach to estimating human oral absorption; and (3) testing this approach in dogs and humans by conducting oral absorption studies on five drugs: cimetidine, furosemide, nadolol, mefenamic acid and propranolol. The intestinal perfusion method for estimating the intestinal wall permeability will be extended to the nonsteady-state case in order to study more variables (pH, drug concentration, solvent flux, nutrient effects) with fewer animals and to obtaining estimates of the absorption rate constant. Measurement of the gastric and intestinal fluid flows and pH will be measured in dogs and man as a function of motility state. These results will be incorporated into a micro-mixing model of the intestine and used to develop a stochastic modeling approach to predicting oral drug delivery. The approach will be tested with five drugs, cimetidine, nadolol, furosemide, mefenamic acid and propranolol which exhibit a range of drug properties: pH dependence, dissolution control, acid/base absorption and first-pass metabolism. The result of this research will fill a very significant pp in the understanding of drug absorption: connecting information at the basic membrane level with oral absorption and bioavailability in man. Estimates of human drug absorption and absorption variability can then be made on the basis of few animal experiments and used to provide more optimal drug therapy to man. The approach is based on determining the underlying fundamental mechanisms controlling drug absorption and once developed will allow estimation of oral drug absorption in disease states that effect the GI tract, leading to more optimal drug therapy of sick patients.

药物吸收的研究通常在两个非常 不同水平：膜/细胞/肠段水平和整体水平 动物/人的水平。前者侧重于膜转运，而后者侧重于膜转运。 着重于对吸收的简单描述。拟议的研究将 发展必要的理解和测试系统的方法， 利用和整合这两个层次的信息。 本研究的具体目标是：（1）开发一种方法， 获得肠粘膜通透性以获得信息 与体内吸收过程更直接相关;（2）开发和 验证生理流模型方法来估计人类口腔 吸收;和（3）通过进行以下测试，在狗和人类中测试这种方法： 五种药物的口服吸收研究：西咪替丁，呋塞米，纳多洛尔， 甲芬那酸和普萘洛尔。 肠灌流法评价肠壁 渗透率将扩展到非稳态的情况下，以研究 更多变量（pH、药物浓度、溶剂通量、营养效应） 用更少的动物和获得吸收率的估计值 常数胃和肠液流量和pH值的测量将 在狗和人中作为运动状态的函数进行测量。这些结果 将被纳入肠道的微混合模型，并用于 开发随机建模方法来预测口服药物递送。 该方法将用五种药物进行测试，西咪替丁，纳多洛尔， 呋塞米、甲芬那酸和普萘洛尔，它们表现出一系列药物 特性：pH依赖性、溶出度控制、酸/碱吸收和 首过代谢 本文的研究成果将填补国内学术界的一个非常重要的空白。 药物吸收的理解：在基础上连接信息 膜水平与人体口服吸收和生物利用度的关系。 人体药物吸收和吸收的可变性，然后可以在 在少量动物实验的基础上，用于提供更优化的药物 该方法是基于确定潜在的 控制药物吸收的基本机制，一旦开发， 允许估计在疾病状态下的口服药物吸收， 胃肠道，导致更优化的药物治疗的病人。