Dressman J B, Fleisher D, Amidon G L
J Pharm Sci. 1984 Sep;73(9):1274-9. doi: 10.1002/jps.2600730922.
A two-tank perfect-mixing tank model was used to stimulate GI absorption. The effect of drug parameters (pK alpha, solubility, and intrinsic wall permeability) and system parameters (pH profile, volume of intestinal contents, and intestinal flow rate) on drug absorption were studied by numerical data stimulation. When the dose did not exceed the solubility of the drug in the intestinal lumen, the fraction absorbed depended on the transit rate relative to the absorption rate and the pK alpha relative to the pH profile, but was independent of drug dose. Saturation of one or both tanks led to dose-dependent absorption. The model was used to simulate absorption of chlorothiazide. Good agreement between simulated and experimental data led to the conclusion that the physical characteristics of chlorothiazide, rather than a saturable transport mechanism at the intestinal wall, may be responsible for the dose-dependent absorption observed for this drug. The model was also used to simulate hydrochlorothiazide absorption. By applying the same system parameters used for chlorothiazide, the model simulation correctly predicted the dose proportionality of hydrochlorothiazide absorption. The lack of dose dependency in this case may be attributed to the higher solubility and pK alpha of hydrochlorothiazide compared with chlorothiazide.
采用双槽完全混合槽模型来模拟胃肠道吸收。通过数值数据模拟研究了药物参数（pKα、溶解度和固有肠壁通透性）和系统参数（pH分布、肠内容物体积和肠流速）对药物吸收的影响。当剂量不超过药物在肠腔内的溶解度时，吸收分数取决于转运速率与吸收速率的比值以及相对于pH分布的pKα，但与药物剂量无关。一个或两个槽的饱和导致剂量依赖性吸收。该模型用于模拟氯噻嗪的吸收。模拟数据与实验数据之间的良好一致性得出结论，氯噻嗪的物理特性而非肠壁上的饱和转运机制可能是该药物观察到的剂量依赖性吸收的原因。该模型还用于模拟氢氯噻嗪的吸收。通过应用与氯噻嗪相同的系统参数，模型模拟正确预测了氢氯噻嗪吸收的剂量比例关系。在这种情况下缺乏剂量依赖性可能归因于氢氯噻嗪与氯噻嗪相比具有更高的溶解度和pKα。
