Takeuchi Rie, Sugano Kiyohiko
Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
ADMET DMPK. 2024 Aug 29;12(4):649-656. doi: 10.5599/admet.2454. eCollection 2024.
The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption.
Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction ( ) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis.
The FeSSIF/ FaSSIF f ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the f ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO).
Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.
食物对口服药物吸收的影响很难根据体外数据进行预测。据报道，进食会降低几种两性离子抗组胺药的口服吸收。然而，这种负面食物效应的机制尚不清楚。本研究的目的是评估两性离子抗组胺药与胆汁微团和食物的结合情况，以此作为食物对其口服药物吸收产生负面效应的一种可能机制。
使用比拉斯汀（BIL）、西替利嗪（CET）、非索非那定（FEX）和奥洛他定（OLO）作为模型药物。据报道，口服给药后BIL、CET、FEX和OLO的进食/空腹AUC比值分别为0.60至0.7、0.92、0.76至0.85和0.84。通过动态透析测量这些药物在含或不含美国食品药品监督管理局早餐匀浆（BFH）的空腹和进食状态模拟肠液（分别含有3 mM和15 mM牛磺胆酸的FaSSIF和FeSSIF）中的游离分数（ ）。
FeSSIF/FaSSIF的f比值分别为0.90（BIL）、0.46（CET）、0.76（FEX）和0.78（OLO）。在存在BFH的情况下，f比值分别降至0.52（BIL）、0.22（CET）、0.39（FEX）和0.44（OLO）。
尽管这些抗组胺药在pH 6.5时为两性离子，但它们仍与胆汁微团结合。胆汁微团和食物结合被认为会对这些药物的口服吸收产生负面食物效应。然而，使用FeSSIF + BFH无法定量预测AUC比值。
