Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability

In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlus^TM) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability. Furthermore, the simulations indicated regional-dependent intestinal permeability of rebamipide, with absorption rank order of jejunum>ileum>duodenum>colon, mainly attributable to segmental mucus differences. Food effect simulations indicated somewhat decreased rebamipide absorption in the fed state, in corroboration with previous reports. Since this anti-ulcer drug is currently examined for additional indications, this work provides important input for future development of rebamipide.