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人胃肠道的药物吸收。提出了一种新的药动学吸收模型，该模型通过体外或原位实验获得的动物数据对人体的吸收过程进行了数学重建。药物本征渗透性的计算及其与人体吸收的相关性通过大鼠肠道灌流实验或体外透皮实验，利用培养的人细胞系单层细胞计算药物渗透的本征参数。在被动吸收药物的情况下，所获得的参数与人体药物吸收之间有很好的相关性。此外，还证明了药物吸收所需的平均时间是考虑药物在人体内的真实吸收过程以及对肠膜的通透性的一个重要参数。建立新的药物吸收动力学模型由于简单的一级吸收模型不能描述药物的整个吸收过程，建立了新的模型，该模型考虑了药物在胃肠道中的运动和水分吸收引起的胃肠道体积变化。3.多肽类药物吸收模型的建立考察了脑啡肽衍生物在大鼠小肠的吸收过程。利用上述药代动力学模型，通过计算脑啡肽衍生物在肠道中的生物利用度，预测了脑啡肽衍生物口服后的生物利用度。该方法有助于论证此类多肽药物口服给药系统的可能性。

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.