Abstract
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 micromixing 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 micromixing 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-glycoprotein 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, which may involve various interactions with intestinal contents or other drugs.
SIGNIFICANCE STATEMENT The newly developed advanced translocation model precisely explains various movements of intestinal contents under fasted and fed conditions, which cannot be adequately described by the current physiological pharmacokinetic models.
Footnotes
- Received January 5, 2021.
- Accepted April 9, 2021.
This work was supported by Japan Agency for Medical Research and Development (AMED) [Grant JP20be0304203] and by the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED [Grant JP20am0101124] (to Y.K.).
S.A. is affiliated with Teijin Pharma Limited, and this study was partly supported by Teijin Pharma Limited. However, Teijin Pharma Limited was not involved in the planning and analysis of this study. No author has an actual or perceived conflict of interest with the contents of this article.
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- Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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