TY - JOUR T1 - A new intestinal model for analysis of drug absorption and interactions considering physiological translocation of contents JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.121.000361 SP - DMD-AR-2021-000361 AU - Satoshi Asano AU - Aoi Yoshitomo AU - Shizuka Hozuki AU - Hiromi Sato AU - Yasuhiro Kazuki AU - Akihiro Hisaka Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/05/06/dmd.121.000361.abstract N2 - Precise prediction of drug absorption is key to the success of new drug development and efficacious pharmacotherapy. In this study, we developed a new absorption model, the advanced translocation model (ATOM), by extending our previous model, the translocation model. ATOM reproduces the translocation of a substance in the intestinal lumen using a partial differential equation with variable dispersion and convection terms to describe natural flow and micro-mixing within the intestine, under not only fasted but also fed conditions. In comparison with ATOM, it was suggested that a conventional absorption model, advanced compartmental absorption and transit model, tends to underestimate micro-mixing in the upper intestine, and it is difficult to adequately describe movements under the fasted and fed conditions. ATOM explains the observed nonlinear absorption of midazolam successfully, with a minimal number of scaling factors. Furthermore, ATOM considers the apical and basolateral membrane permeabilities of enterocytes separately and assumes compartmentation of the lamina propria, including blood vessels, to consider intestinal blood flow appropriately. ATOM estimates changes in the intestinal availability caused by drug interaction associated with inhibition of CYP3A and P-gp in the intestine. Additionally, ATOM can estimate the drug absorption in the fed state considering delayed intestinal drug flow. Therefore, ATOM is a useful tool for the analysis of local pharmacokinetics in the gastrointestinal tract, especially for the estimation of nonlinear drug absorption that may involve various interactions with intestinal contents or other drugs. Significance Statement The advanced translocation model (ATOM) was newly developed that precisely explains various movements of intestinal contents including the fasted and fed conditions which cannot be adequately described by the current physiological pharmacokinetic models. ER -