Quantitative analysis of the impact of membrane permeability on intestinal first-pass metabolism of CYP3A substrates

IF 1.7 4区医学 Q3 PHARMACOLOGY & PHARMACY

Biopharmaceutics & Drug Disposition Pub Date : 2023-12-12 DOI:10.1002/bdd.2379

Yugo Yasugi, Yoshiyuki Shirasaka, Ikumi Tamai

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Abstract

The aim of this study was firstly to investigate the effect of membrane permeability on the intestinal availability (F_g) of 10 cytochrome P450 3A4 substrates with differing permeability (P_app) and metabolic activity (CL_int) using Madin-Darby canine kidney II (MDCKII) cells expressing human CYP3A4 (MDCKII/CYP3A4 cells), and secondly to confirm the essential factors by simulations. A membrane permeation assay using MDCKII/CYP3A4 cells showed a significant correlation between human intestinal extraction ratio (ER) (E_g (=1 − F_g)) and in vitro cellular ER (r = 0.834). This relationship afforded better predictability of E_g values than the relationship between E_g and CL_int,HIM values obtained from human intestinal microsomes (r = 0.598). An even stronger correlation was observed between 1 − F_a·F_g and ER (r = 0.874). Simulation with a cellular kinetic model indicated that ER is sensitive to changes of PS_passive and CL_int values, but not to the intracellular unbound fraction (f_u,cell) or P-gp-mediated efflux (PS_P − gp). It may be concluded that, based on the concentration–time profile of drugs in epithelial cells, transmembrane permeability influences F_g (or ER) and drug exposure time to metabolizing enzymes for P450 substrate.

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膜渗透性对 CYP3A 底物肠道首过代谢影响的定量分析

本研究首先利用表达人CYP3A4的Madin-Darby犬肾II (MDCKII/CYP3A4细胞)细胞(MDCKII/CYP3A4细胞)，研究膜通透性对10种不同通透性(Papp)和代谢活性(CLint)的细胞色素P450 3A4底物肠道利用度(Fg)的影响，然后通过模拟实验确定其中的关键因素。采用MDCKII/CYP3A4细胞进行的膜渗透试验显示，人肠道提取率(ER) (Eg(=1−Fg))与体外细胞ER (r = 0.834)之间存在显著相关性。这种关系比Eg与人肠微粒体的CLint、HIM值之间的关系(r = 0.598)更能预测Eg值。1 - Fa·Fg与ER之间的相关性更强(r = 0.874)。细胞动力学模型模拟表明，内质网对ppaspassive和CLint值的变化敏感，但对胞内未结合分数(fu,cell)或p- gp介导的外排(PSP−gp)不敏感。根据药物在上皮细胞中的浓度-时间分布，可以得出结论，跨膜通透性影响Fg(或ER)和药物暴露于P450底物代谢酶的时间。

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

Biopharmaceutics & Drug Disposition 医学-药学

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods