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

Abstract

AbstractThe aim of this study was firstly to investigate the effect of membrane permeability on the intestinal availability (Fg) of 10 cytochrome P450 3A4 substrates with differing permeability (Papp) and metabolic activity (CLint) 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) (Eg (=1 − Fg)) and in vitro cellular ER (r = 0.834). This relationship afforded better predictability of Eg values than the relationship between Eg and CLint,HIM values obtained from human intestinal microsomes (r = 0.598). An even stronger correlation was observed between 1 − Fa·Fg and ER (r = 0.874). Simulation with a cellular kinetic model indicated that ER is sensitive to changes of PSpassive and CLint values, but not to the intracellular unbound fraction (fu,cell) or P‐gp‐mediated efflux (PSP − gp). It may be concluded that, based on the concentration–time profile of drugs in epithelial cells, transmembrane permeability influences Fg (or ER) and drug exposure time to metabolizing enzymes for P450 substrate.