Ando Hirotaka, Hisaka Akihiro, Suzuki Hiroshi
Department of Pharmacy (H.A., H.S.) and Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (A.H.).
Department of Pharmacy (H.A., H.S.) and Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (A.H.)
Drug Metab Dispos. 2015 Apr;43(4):590-602. doi: 10.1124/dmd.114.060038. Epub 2015 Jan 23.
This study aimed to construct a new local pharmacokinetic model of gastrointestinal absorption, the translocation model (TLM), using an anatomically relevant, minimally segmented structure to explain linear and nonlinear intestinal absorption, metabolism, and transport. The TLM was based on the concept of a single absorption site that flexibly moves, expands, and shrinks along with the length of the gastrointestinal tract after the intake of an oral dose. The structure of the small intestine is continuous, and various time- and location-dependent issues are freely incorporated in the analysis. Since the model has only one absorption site, understanding and modification of factors affecting absorption are simple. The absorption site is composed of four compartments: solid drug in the lumen, solution drug in the lumen, concentration in the enterocytes, and concentration in the lamina propria. The lamina propria includes the blood capillaries. Blood flow in the absorption site of the lamina propria appropriately accounts for the absorption. In the TLM, the permeability of the apical membrane and that of the basolateral membrane are distinct. By considering plicate, villi, and microvilli expansions of the surface area, the apparent permeability measured in Caco-2 experiments was converted to the effective permeability in vivo. The intestinal availability, bioavailability, and dose product of intestinal availability and absorption rate relationship of the model drugs were well explained using the TLM. The TLM would be a useful tool for the consideration of local pharmacokinetics in the gastrointestinal tract in various situations.
本研究旨在构建一种新的胃肠道吸收局部药代动力学模型——转运模型（TLM），该模型采用与解剖结构相关的最小分段结构来解释线性和非线性肠道吸收、代谢及转运过程。TLM基于单一吸收位点的概念，口服给药后，该吸收位点会沿着胃肠道长度灵活移动、扩张和收缩。小肠结构是连续的，分析过程中可自由纳入各种时间和位置依赖性问题。由于该模型只有一个吸收位点，因此对影响吸收的因素进行理解和修正都很简单。吸收位点由四个隔室组成：肠腔内的固体药物、肠腔内的溶液药物、肠细胞内的浓度以及固有层内的浓度。固有层包括毛细血管。固有层吸收位点的血流可适当解释吸收情况。在TLM中，顶端膜和基底外侧膜的通透性是不同的。通过考虑皱襞、绒毛和微绒毛表面积的扩张，将Caco-2实验中测得的表观通透性转化为体内有效通透性。使用TLM可以很好地解释模型药物的肠道可利用性、生物利用度以及肠道可利用性与吸收速率关系的剂量乘积。TLM将成为在各种情况下考虑胃肠道局部药代动力学的有用工具。
