Akiyama Yoshiyuki, Ito Soichiro, Fujita Takuya, Sugano Kiyohiko
Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Eur J Pharm Sci. 2020 Dec 1;155:105543. doi: 10.1016/j.ejps.2020.105543. Epub 2020 Sep 12.
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 (P) 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 P 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.
本研究的目的是定量预测胆汁微团结合对亲水性阳离子药物口服吸收所诱导的负面食物效应。根据禁食和进食条件下的实验性Caco-2通透性数据（P），计算了12种模型药物（7种叔胺、3种季铵盐和2种中性药物）的固有膜通透性和胆汁微团未结合分数。根据这些输入数据，使用基于机制的口服吸收模型——胃肠道统一理论框架预测吸收剂量分数（Fa）。然后将预测的Fa比值（进食/禁食）与体内血浆浓度-时间曲线下面积比值（AUCr）进行比较。叔胺和中性药物的AUCr值得到了适当预测（绝对平均倍数误差（AAFE）=1.19），而季铵盐的AUCr值则被明显低估（AAFE=4.70）。P比值（进食/禁食）对AUCr的预测定量性较差（叔胺和中性药物的AAFE=1.30）。本研究结果将有助于更好地理解食物对口服药物吸收的负面效应。
