ORAL DRUG DELIVERY AND BIOAVAILABILITY--AIDS

药物的吸收和生物利用度在很大程度上是根据经验来处理的。 基于对动物和/或人类研究的事后分析。 这无疑是由于药物治疗过程的复杂性。 从胃肠道吸收和代谢。 拟议 研究项目的长期目标是开发一种 基于生理学的综合运输模型 胃肠道，当结合适当的结果， 动物和人体实验的基本基础生理 过程，将预测药物在人体内的吸收。 当完全 开发，该方法将是机械的，并使预测 平均血浆水平以及预期的受试者内和受试者间变异 基于所测量的潜在生理变化 参数，如胃排空率，肠通过率， 肠pH值和渗透性，在禁食和进食状态。 的 拟议项目的具体目标是：（1）制定一个通用的 用于估计药物吸收程度的宏观模型 胃肠道，包括渗透性，稳定性，酶 活性、溶解度和溶出速率，测量所需的 动物模型和/或人类中的参数，并比较估计的 吸收程度和变化与ddI的观察结果， 膦甲酸、西咪替丁和呋塞米或纳多洛尔;（2）延长 药物溶出到表面活性剂溶液中的传输模型， 并将该模型应用于药物浓度的预测 水不溶性药物在人体内的吸收;（3）形成结合， 考来烯胺功效的转运和生理模型， 考来替泊树脂，确定适当的体外测量， 与体内疗效相关，并将该药效学模型应用于 提高这些药物产品的功效;（4）延长 胃肠道肝脏生理血流模型 β受体阻滞剂普萘洛尔和NSAID的生物利用度变异性 布洛芬从狗到人;（5）开发一种生理微- 胃肠道的混合模型，包括运输， 溶解和药物透过肠膜。 的 模型将解释肠道通透性的变化， 胃肠道以及流速和管腔环境 变化，即，pH、缓冲表面活性剂和脂质含量以及酶 浓度的 该模型还将包括胃肠道 与胃排空和肠道转运相关的变化， 禁食和进食状态以及运输中的相位相关变化， 管腔内容物 当这种机械方法得到充分发展时， 药物吸收和药物吸收的变异性在人类的基础上， 关于药物和剂型的最低数量的基本信息。 此外，当充分发展时，机械方法将具有 能够预测药物吸收和血浆浓度的进一步优点是 在改变胃肠道生理功能的疾病状态下， 变量 这将有助于对病人进行更优化的治疗， 如艾滋病患者。

Drug absorption and bioavailability is largely treated on an empirical basis with after-the-fact analysis of studies in animals and/or humans. This is undoubtedly due to the complexity of processes involved in drug absorption and metabolism from the gastrointestinal tract. The proposed research project has as its long-term objective the development of a comprehensive physiologically based transport model of the gastrointestinal tract which, when combined with appropriate results of animal and human experiments on the basic underlying physiological processes, will be predictive of drug absorption in humans. When fully developed, the approach will be mechanistic and enable the prediction of mean plasma levels as well as expected intra- and intersubject variation based on the measured variation of the underlying physiological parameters, such as gastric emptying rate, intestinal transit rate, intestinal pH and permeability, in both the fasted and fed-states. the specific aims of the proposed project are: (1) develop a general macroscopic model for estimating the extent of drug absorption from the gastrointestinal tract that includes permeability, stability, enzymatic activity, solubility and dissolution rate, measure the required parameters in animal models and/or humans and compare the estimated extent and variation of absorption with the observed results for ddI, foscarnet, cimetidine, and furosemide or nadolol; (2) extend the transport model for drug dissolution into surfactant solutions to emulsions and apply this model to estimating the extend of drug absorption for water insoluble drugs in humans; (3) develop a binding, transport and physiological model for the efficacy of cholestyramine and colestipol resins, determine the appropriate in vitro measurements to correlate with in vivo efficacy and apply this pharmacodynamic model to improving the efficacy of these drug products; (4) extend the gastrointestinal hepatic physiological flow model for the systemic bioavailability variability of the beta-blocker propranolol and the NSAID ibuprofen from dogs to humans; and (5) develop a physiological micro- mixing model of the gastrointestinal tract, including transit, dissolution and drug permeation through the intestinal membrane. The model will account for intestinal permeability changes down the gastrointestinal tract as well as flow rate and luminal environment changes, i.e., pH, buffer surfactant and lipid content and enzyme concentrations. The model will also include the gastrointestinal variations associated with gastric emptying and intestinal transit in the fasted and fed-state and the phase related variations in transit and luminal content. When fully developed this mechanistic approach will allow the estimation of drug absorption and drug absorption variability in humans based on a minimum amount of basic information on the drug and dosage form. Furthermore, when fully developed, a mechanistic approach will have the further advantage of being able to predict drug absorption and plasma levels in diseased states that alter the gastrointestinal physiological variables. This will aid in more optimal treatment of sick patients, such as those with AIDS.