Prediction of negative food effect induced by bile micelle binding on oral absorption of hydrophilic cationic drugs

The purpose of the present study was to quantitatively predict the negative food effect induced by bile micelle binding on the oral absorption of hydrophilic cationic drugs. The intrinsic membrane permeability and bile micelle unbound fraction of 12 model drugs (7 tertiary amines, 3 quaternary ammoniums, and 2 neutral drugs) were calculated from the experimental Caco-2 permeability data ( Papp ) under fasted and fed conditions. From these input data, the fraction of a dose absorbed ( Fa ) was predicted using the gastrointestinal unified theoretical framework, a mechanism-based oral absorption model. The predicted Fa ratio (fed/fasted) was then compared with the in vivo fed/fasted area under the plasma concentration–time curve ratio (AUCr). The AUCr values of tertiary amines and neutral drugs were appropriately predicted (absolute average fold error (AAFE) = 1.19), whereas those of quaternary ammoniums were markedly underestimated (AAFE = 4.70). The Papp ratio (fed/fasted) predicted AUCr less quantitatively (AAFE = 1.30 for tertiary amines and neutral drugs). The results of the present study would lead to a better understanding of negative food effect on oral drug absorption.