来自人类肠道有机体的坚固和可重复的单层模型,用于分析药物吸收
Kai Tanaka1, Tatsuki Mochizuki2, Shogo Baba3
1Translational Research Division, Chugai Pharmaceutical Co., Ltd, 216 Totsuka Totsuka-Ku Yokohama, Kanagawa, Japan. tanaka.kai11@chugai-pharm.co.jp.
Scientific reports
|April 3, 2025
概括
这项研究引入了人类肠道有机体模型,用于预测口服药物吸收. 这种可重复的模型准确地预测了药物透性,提高了药物开发成功率.
科学领域:
- 生物技术是生物技术.
- 药物开发 药物开发
- 胃肠病学 胃肠病学
背景情况:
- 对口服药物吸收的准确预测对于成功的药物开发至关重要.
- 现有的体外模型往往缺乏可靠的药物吸收预测所需的生理相关性,稳定性和可重复性.
研究的目的:
- 为研究药物吸收开发一种可复制和坚固的人体肠道有机物衍生的单层模型.
- 验证模型的生理相关性和药物透性的预测能力.
主要方法:
- 产生人类肠道有机物衍生的单层培养物.
- 评估基因表达,屏障功能,载体和酶活性以及核受体活性.
- 在模型中对药物透性的相关性分析与人类的分量吸收 (Fa) 和分量吸收第一通代谢 (FaFg) 值.
主要成果:
- 在关键的药物吸收相关功能中,有机体模型密切模仿了初级肠细胞.
- 对于19种药物,观察到模型透度和人类的Fa值之间存在强烈的相关性 (R2 = 0.88).
- 包括CYP3A基质在内的9种药物中的7种估计的人类FaFg值在与建模和模拟相结合时在人类范围的1.5倍之内.
结论:
- 开发的人类肠道有机物衍生单层模型为药物吸收研究提供了可重复和生理相关的平台.
- 该模型显示了改善口服药物吸收预测的巨大潜力,弥合了临床前和临床研究之间的差距.
- 该模型在药物发现中的应用可以通过提供更可靠的临床前数据来提高口服药物开发的成功率.
相关概念视频
01:16Methods for Studying Drug Absorption: In vitro
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In vitro experiments are crucial for understanding the transport and absorption of drugs through biological materials. These studies employ varied methods such as the diffusion cell method, the everted sac technique, and the everted ring technique.
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
184
01:09Methods for Studying Drug Absorption: In situ
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In situ experiments, such as the Doluisio method and Single-Pass Perfusion technique, provide critical insights into drug uptake by simulating in vivo conditions for drug absorption.
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
187
01:23Factors Influencing Drug Absorption: Anatomical Parameters
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Drug absorption involves the movement of drugs from the point of administration into the systemic circulation. Initially, Gastrointestinal (GI) motility propels the drug through the digestive tract and into the stomach. However, the stomach's high acidity and limited surface area restrict its role in drug absorption for most drugs. The drug then moves from the stomach to the small intestine via gastric emptying, which can be slowed by various factors, including interactions with other...
167