Quantitative analysis of the impact of membrane permeability on intestinal first-pass metabolism of CYP3A substrates

The aim of this study was firstly to investigate the effect of membrane permeability on the intestinal availability (F_g) of 10 cytochrome P450 3A4 substrates with differing permeability (P_app) and metabolic activity (CL_int) using Madin-Darby canine kidney II (MDCKII) cells expressing human CYP3A4 (MDCKII/CYP3A4 cells), and secondly to confirm the essential factors by simulations. A membrane permeation assay using MDCKII/CYP3A4 cells showed a significant correlation between human intestinal extraction ratio (ER) (E_g (=1 − F_g)) and in vitro cellular ER (r = 0.834). This relationship afforded better predictability of E_g values than the relationship between E_g and CL_int,HIM values obtained from human intestinal microsomes (r = 0.598). An even stronger correlation was observed between 1 − F_a·F_g and ER (r = 0.874). Simulation with a cellular kinetic model indicated that ER is sensitive to changes of PS_passive and CL_int values, but not to the intracellular unbound fraction (f_u,cell) or P-gp-mediated efflux (PS_P − gp). It may be concluded that, based on the concentration–time profile of drugs in epithelial cells, transmembrane permeability influences F_g (or ER) and drug exposure time to metabolizing enzymes for P450 substrate.