Predicting Food Effect On Oral Drug Absorption For Solubility-Epithelial Membrane Permeation-Limited Cases With Bile...

The purpose of this study was to investigate the theoretical and in vitro experimental prediction of food effects on oral drug absorption, focusing on solubility-epithelial membrane permeation-limited cases (SL-E).

Bosentan, fidaxomicin, pranlukast, and rifaximin were employed as model SL-E drugs. Celecoxib and danazol were employed as solubility-unstirred water layer permeation-limited cases (SL-U) for comparison. Theoretical predictions of food effects were based on the rate-limiting steps of the fraction of a dose absorbed (Fa) (FaRLS) (Fa rate-limiting step). μFLUX was used as a dissolution-permeation flux (J_μFLUX) experiment. Fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively) were employed as the donor solution.

For all SL-E drugs, the food effect on Fa was theoretically predicted to be 1.2, irrespective of bile micelle solubilization (FaSSIF/FeSSIF: bosentan (2.1), fidaxomicin (2.3), pranlukast (9.1), and rifaximin (3.5)). Theoretically, an increase in solubility by bile micelles is counterbalanced by a decrease in effective permeability (P_eff) due to a decrease in the free fraction (P_eff is defined based on unbound + bound drug concentration (C_D)). This prediction was consistent with the clinical data (fed/fasted AUC ratio: 1.1, 1.0, 1.3, and 1.6, respectively). In μFlux, even though C_D was markedly higher in FeSSIF than in FaSSIF (1.9, 3.1, 20, and 3.3-fold, respectively), J_μFLUX was less enhanced (0.91, 0.81, 2.4, and 0.81-fold, respectively). For the SL-U drugs, as theoretically expected, J_μFLUX was increased as C_D was increased, which was consistent with the clinical data.

FaRLS appropriately predicted the food effect for the SL-E drugs. The mechanism was experimentally confirmed by μFlux.