ORAL DRUG DELIVERY AND BIOAVAILABILITY

对药物吸收的研究通常是在两个非常 不同水平：膜/细胞/肠段水平和整体 动物/人的水平。前者侧重于膜转运，后者侧重于膜转运 重点介绍了吸收的简单描述。拟议的研究将 发展必要的理解并测试系统的方法 利用和整合这两个层面的信息。 拟议研究的具体目标是：(1)开发一种方法 获取肠粘膜通透性以获取信息 与体内吸收过程更直接相关；(2)发展和 验证一种估计人类口腔的生理流动模型方法 吸收；以及(3)在狗和人身上测试这种方法 西咪替丁、速尿、纳多洛尔等5种药物的口服吸收研究 甲芬酸和心得安。 肠道灌注法测定肠壁厚度的研究 将渗透率推广到非稳态情况，以便于研究 更多变量(pH、药物浓度、溶剂通量、营养效应) 用更少的动物，并获得吸收率的估计 常量。胃液和肠液流量和pH值的测量 在狗和人身上作为运动状态的函数进行测量。这些结果 将被整合到肠道的微型混合模型中，并用于 开发一种预测口服药物释放的随机建模方法。 该方法将用五种药物进行测试，西咪替丁，纳多洛尔， 呋塞米、甲芬酸和普奈洛尔 性能：pH依赖性、溶出度控制、酸碱吸收和 首过新陈代谢。 这项研究的结果将填补一个非常重要的pp在 对药物吸收的理解：在基础上连接信息 人体口服吸收和生物利用度的膜水平。估计数 人体对药物的吸收和吸收的可变性可以在 在少数动物实验的基础上，用于提供更理想的药物 对人类的治疗。该方法基于确定潜在的 控制药物吸收的基本机制，一旦开发出来，将 允许估计影响疾病状态的口服药物吸收 GI途径，为病人带来更理想的药物治疗。

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.