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A New Physiologically Based Pharmacokinetic Model for the Prediction of Gastrointestinal Drug Absorption: Translocation Model

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.