Significance of basal membrane permeability of epithelial cells in predicting intestinal drug absorption

Drug absorption from the gastro-intestinal tract is often restricted by efflux transport by P-glycoprotein (P-gp) 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.