Drug absorption from the gastro-intestinal tract is often restricted by efflux transport by P-glycoprotein (Pgp) and metabolism by cytochrome P450 (CYP) 3A4. Both localize in the epithelial cells and thus their activities are directly affected by the intracellular drug concentration which should be regulated by the ratio of permeability between apical (A) and basal (B) membranes. In this study, using Caco-2 cells with forced expression of CYP3A4, we assessed the transcellular permeation of A-to-B and B-to-A directions and the efflux from the preloaded cells to the both sides of 12 representative P-gp or CYP3A4 substrate drugs, and obtained the parameters for permeabilities, transport, metabolism, and unbound fraction in the enterocytes (f ent ) using simultaneous and dynamic model analysis. The membrane permeability ratios for B to A (R BA ) and f ent varied by 8.8-fold and by more than 3,000-fold, respectively, among the drugs. The R BA values for digoxin, repaglinide, fexofenadine, and atorvastatin were greater than 1. 0 (3.44, 2.39, 2.27, and 1.90, respectively) in the presence of a P-gp inhibitor, thus suggesting the potential involvement of transporters in the B membrane. The K m for quinidine for P-gp transport was 0.077 µM for the intracellular unbound concentration. These parameters were used to predict overall intestinal availability (F A F G ) by applying an intestinal pharmacokinetic model, ATOM, in which permeability of A and B membranes accounted separately. The model predicted changes in the absorption location for P-gp substrates according to its inhibition, and F A F G values of 10/12 drugs, including quinidine at varying doses, were explained appropriately.

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, This article has not been copyedited and formatted. The final version may differ from this version.

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