PREDICTION AND OPTIMIZATION OF DRUG ABSORPTION FROM THE GASTRO-INTESTINAL TRACT

本研究旨在预测和改善口服给药后药物在人体胃肠道的吸收。提出了一种新的药物动力学吸收模型，该模型根据体外或原位实验获得的动物数据，以数学方式重建人体吸收过程.药物固有渗透系数的计算及其与人体吸收的相关性通过大鼠小肠灌流实验和体外单层人细胞渗透实验，计算了药物的固有渗透系数。在被动吸收药物的情况下，观察到良好的相关性之间获得的参数和人体药物吸收。此外，还证明了平均吸收所需时间是考虑药物在人体内真实的吸收过程以及肠膜通透性的重要参数.新的药物吸收动力学模型的建立由于简单的一级吸收模型不能描述药物的整个吸收过程，因此建立了新的模型，该模型考虑了药物在胃肠道中的沿着运动，以及水吸收引起的胃肠道体积变化。3.肽类药物吸收模型的建立研究了脑啡肽衍生物在大鼠小肠中的吸收过程。通过计算脑啡肽衍生物的降解清除率和肠道渗透清除率，预测了脑啡肽衍生物口服给药后的生物利用度。该方法可用于验证此类肽类药物口服给药系统的可行性。

This research was undertaken to predict and improve the drug absorption from human GI tract after oral administration. New pharmacokinetic absorption model was proposed in which the human absorption processes were reconstituted mathematically from the animal data obtained in in vitro or in situ experiments.1. Calculation of intrinsic drug permeability and its correlation with human absorptionIntrinsic parameters for drug permeation were calculated from rat intestinal perfusion experiment or in vitro permeation experiment using the monolayr of cultured human cell line. In the case of passively absorbed drugs, good correlation was observed between the obtained parameters and human drug absorption. In addition, it was proved that the mean time required for drug absorption is an important parameter to consider the real absorption process in human, as well as the permeability to intestinal membrane.2. Constitution of new pharmacokinetic model for drug absorptionSince the simple first-order absorption model failed to describe the whole absorption process of drugs, the new model was constituted which takes into consider the drug movement along the GI tract, the volume change in the GI tract due to water absorption. It was proved that the new model is useful to describe the blood concentration profiles of drugs after oral administration.3.Constitution of absorption model for peptide drugsThe absorption processes of enkephalin derivatives in rat small intestine were investigated. By calculating the clearances for the degradation and the permeation from the intestinal tract, the bioavailability of enkephalin derivatives after oral administration was predicted using above pharmacokinetic model. This method was useful to demonstrate the possibility of oral delivery system for such peptide drugs.