人体体单层:用于调查口服药物处置的新型,功能稳定的模型
Christopher Arian1, Eimear O'Mahony2, James W MacDonald3
1Department of Pharmaceutics, University of Washington, United States.
概括
人体肠单层为研究口服药物吸收和代谢提供了一个新的体外模型. 这种先进的模型维持了肠道屏障功能和代谢活动长达42天,改善了药物处置预测.
科学领域:
- 生物医学工程 生物医学工程
- 药物发现 药物发现 药物发现
- 胃肠病学 胃肠病学
背景情况:
- 开发精确的体外模型来处理口服药物至关重要.
- 现有的模型往往缺乏结合肠道吸收和新陈代谢评估能力.
- 人类肠道有机体 (肠体) 是一个潜在的解决方案.
研究的目的:
- 评估人类肠单层作为一种体外模型,用于评估肠道药物吸收和第一通代谢.
- 为了确定体单层的长期屏障完整性和代谢功能.
- 在长时间的培养期内研究药物代谢酶和载体 (DMET) 表达和功能.
主要方法:
- 人类十二指肠干细胞被培养在Transwell®插件上形成体单层.
- 使用RNA-seq和免疫细胞化学证实了细胞分化,形态和紧结蛋白表达.
- 测量了体电阻 (TEER) 和细胞透性,以评估屏障完整性.
- 在42天的时间里,在各种条件下评估了P450 3A4 (CYP3A) 细胞染色体的活性.
主要成果:
- 体单层成功分化为富含体细胞的群体,具有适当的形态.
- 实现了稳定和持久的屏障完整性,由高TEER和低透度表明,长达42天.
- 在整个42天的培养期内,功能性CYP3A活性得到证实,证明了持续的代谢能力.
- 这项研究是首次评估在12天以上培养的体中DMET功能.
结论:
- 人体肠状单层代表了一个强大的,持久的ex vivo模型,用于研究肠道药物吸收和代谢.
- 该模型在长时间内结合的屏障功能和代谢活动,与传统的体外系统相比,具有显著的优势.
- 这种先进的模型对量化预测口服药物的体内行为具有前景.
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.
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01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
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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.
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227
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
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01:19One-Compartment Open Model for IV Bolus Administration: General Considerations
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01:27Factors Influencing Drug Absorption: Drug Dissolution
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The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
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