Analysis of physiological factors regulating oral absorption behaviors of drugs and its application to prediction of plasma concentration-time profile

为了预测药物在肠粘膜中的代谢和/或分泌行为，我们将P-糖蛋白(P-PG)作为一种分泌机制，将细胞色素P3A(CyP3A)作为一种代谢机制，并试图建立定量评价系统来评价P-糖蛋白和细胞色素P3A对药物口服吸收行为的影响。地塞米松(DEX)25~100 mg/kg/d灌胃，连续2天，制备高水平的P-gp和CyP3A大鼠。通过测定分离肠片上罗丹明123的分泌量和微粒体中6β-0H的睾酮生成量，证实P-gp和细胞色素P3A的高表达。此外，我们开发了一种血管灌流的肠-肝制剂，使其能够同时评价小肠的吸收、分泌、代谢和肝脏的代谢。用VASSU…成功地评价了奎尼丁的吸收动力学另一方面，P-gp和/或CyP3A的许多底物都是众所周知的高亲脂性和较差的水溶性。因此，我们尝试基于胃肠转运吸收模型(GITA模型)来预测难溶药物口服粉剂后的吸收行为。灰黄霉素被归入生物制药分类系统II类，作为模型化合物。利用日本药典(JP)1号溶液、日本药典(JP)2号溶液、禁食状态模拟肠液(FaSSIF)和饲喂状态模拟肠液(FeSSIF)等几种现有的溶出介质，将溶出过程假定为一级动力学，将其纳入GITA模型，并测定了溶出速率常数。然而，用这些溶出速率常数得到的模拟曲线与观察到的灰黄霉素的血药浓度曲线并不完全一致。为此，我们开发了两种新的溶出介质，即介质反射体内溶出度(MREVID)1和2。然后，基于GITA模型，利用新介质获得的溶出速率常数预测了灰黄霉素口服后的血药浓度-时间分布。因此，利用MREVID2得到的溶解速率常数计算的模拟曲线提供了对观察线的最佳描述，该模拟曲线足以预测Cmax和AUC，尽管观察值和计算值之间存在微小差异。较少

In order to predict the oral absorption behaviors of drugs subjected to metabolism and/or secretion in the intestinal mucosa, we focused on P-glycoprotein (P-pg) as a secretion mechanism, and Cyp3A as a metabolism mechanism, and tried to develop the quantitative evaluation systems which allow us to estimate the effects of P-gp and Cyp3A on the oral absorption behavior. With oral dosing of dexamethasone (DEX) at 25-100 mg/kg/day for 2 days, rats having P-gp and Cyp3A at higher levels were prepared. High expression of P-gp and Cyp3A were recognized by estimating the secretion of rhodamine 123 in isolated intestinal sheets and the generation of 6β-0H of testosterone in microsome, respectively. Furthermore, we developed a vascularly perfused intestine-liver preparation, which makes it possible to evaluate the absorption, secretion, metabolism in the small intestine and the metabolism in the liver at the same time. The absorption kinetics of quinidine was successfully evaluated with a vascu … More larly perfused intestine-liver preparation.On the other hand, many substrates for P-gp and/or Cyp3A are well known to be high lipophilic and poorly water-soluble. Therefore, we tried to predict the absorption behaviors of poorly water-soluble drugs after oral dosing as powders based on Gastrointestinal-Transit-Absorption model (GITA model). Griseofulvin, classified into Biopharmaceutics Classification System class II, was selected as a model compound. Dissolution process, assumed to obey the first-order kinetics, was incorporated into GITA model and the dissolution rate constants were determined by utilizing several existing media such as Japanese Pharmacopeia (JP) 1st solution, 2nd solution, fasted-state simulated intestinal fluids (FaSSIF) and fed-state simulated intestinal fluids (FeSSIF). However, simulated lines obtained with these dissolution rate constants were not in good agreement with the observed profile of plasma concentration of griseofulvin at all. Therefore, we developed a couple of new media, medium reflection in-vivo dissolution (MREVID) 1 and 2. Then, based on GITA model, the plasma concentration-time profile of griseofulvin after oral administration was predicted by utilizing the dissolution rate constants obtained with the new media. As a result, a simulation curve calculated by utilizing the dissolution rate constant obtained with MREVID 2 provided the best description of the observed line, which was good enough to predict Cmax and AUC although there was a little difference in Tmax between the observed and calculated values. Less