Food and bile micelle binding of zwitterionic antihistamine drugs.

IF 3.4 Q2 CHEMISTRY, MEDICINAL
ADMET and DMPK Pub Date : 2024-08-29 eCollection Date: 2024-01-01 DOI:10.5599/admet.2454
Rie Takeuchi, Kiyohiko Sugano
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引用次数: 0

Abstract

Background and purpose: 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.

Experimental approach: 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 (f u) 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.

Key results: The FeSSIF/ FaSSIF fu ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the fu ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO).

Conclusion: 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.

食物与胆汁胶束结合的齐聚物抗组胺药物。
背景和目的:根据体外数据预测食物对口服药物吸收的影响具有挑战性。据报道,食物摄入会降低几种齐聚物抗组胺药物的口服吸收。然而,这种食物负效应的机制尚不清楚。本研究的目的是评估齐聚物抗组胺药物的胆汁胶束和食物结合,作为食物对其口服药物吸收产生负面影响的可能机制:实验方法:以比拉斯汀(BIL)、西替利嗪(CET)、非索非那定(FEX)和奥洛帕定(OLO)为模型药物。据报道,BIL、CET、FEX 和 OLO 口服后的进食/空腹 AUC 比值分别为 0.60 至 0.7、0.92、0.76 至 0.85 和 0.84。通过动态透析法测定了空腹和进食状态模拟肠液(FaSSIF和FeSSIF,分别含有3毫摩尔和15毫摩尔牛磺胆酸)(含或不含FDA早餐匀浆(BFH))中这些药物的未结合部分(f u):主要结果:FeSSIF/ FaSSIF fu 比率分别为 0.90(BIL)、0.46(CET)、0.76(FEX)和 0.78(OLO)。在 BFH 的存在下,fu 比分别降至 0.52(BIL)、0.22(CET)、0.39(FEX)和 0.44(OLO):结论:尽管抗组胺药物在 pH 值为 6.5 时为齐聚物,但它们仍与胆汁胶束结合。胆汁胶束和食物结合被认为会对这些药物的口服吸收产生负面影响。然而,使用 FeSSIF + BFH 无法定量预测 AUC 比值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ADMET and DMPK
ADMET and DMPK Multiple-
CiteScore
4.40
自引率
0.00%
发文量
22
审稿时长
4 weeks
期刊介绍: ADMET and DMPK is an open access journal devoted to the rapid dissemination of new and original scientific results in all areas of absorption, distribution, metabolism, excretion, toxicology and pharmacokinetics of drugs. ADMET and DMPK publishes the following types of contributions: - Original research papers - Feature articles - Review articles - Short communications and Notes - Letters to Editors - Book reviews The scope of the Journal involves, but is not limited to, the following areas: - physico-chemical properties of drugs and methods of their determination - drug permeabilities - drug absorption - drug-drug, drug-protein, drug-membrane and drug-DNA interactions - chemical stability and degradations of drugs - instrumental methods in ADMET - drug metablic processes - routes of administration and excretion of drug - pharmacokinetic/pharmacodynamic study - quantitative structure activity/property relationship - ADME/PK modelling - Toxicology screening - Transporter identification and study
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