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代谢和/或分泌后的口服吸收行为，我们以P-糖蛋白（P-pg）为分泌机制，以Cyp 3A为代谢机制，尝试建立定量评价系统，以评价P-gp和Cyp 3A对口服吸收行为的影响。通过口服给予25-100 mg/kg/天的地塞米松（DEX）2天，制备具有较高水平的P-gp和Cyp 3A的大鼠。P-gp和Cyp 3A的高表达分别通过测定离体肠片中罗丹明123的分泌和微粒体中睾酮的6β-OH的产生来确认。此外，我们还开发了一种血管灌注的小肠-肝脏制剂，这使得可以同时评价小肠中的吸收、分泌、代谢和肝脏中的代谢。用血管吸收动力学法研究了奎尼丁的吸收动力学 关于我们 另一方面，众所周知，P-gp和/或Cyp 3A的许多底物是高度亲脂性的和水溶性差的。因此，我们尝试基于胃肠道-转运-吸收模型（GITA模型）预测水溶性差的药物以粉末形式口服给药后的吸收行为。灰黄霉素，归类为生物药剂学分类系统II类，被选为模型化合物。将溶出过程假设为一级动力学，并将其纳入GITA模型，利用日本药典（JP）第1溶液、第2溶液、禁食状态模拟肠液（FaSSIF）和进食状态模拟肠液（FeSSIF）等几种现有介质测定溶出速率常数。然而，这些溶出速率常数得到的模拟线并不与灰黄霉素的血浆浓度的观察曲线在所有良好的协议。因此，我们开发了几种新介质，介质反射体内溶解（MREVID）1和2。基于GITA模型，利用新介质的溶出速率常数预测口服给药后灰黄霉素的血药浓度-时间曲线。因此，通过使用MREVID 2获得的溶出速率常数计算的模拟曲线提供了对观察到的线的最佳描述，其足以预测Cmax和AUC，尽管观察值和计算值之间的Tmax存在微小差异。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