人体肠状单层作为Ussing室和Caco-2单层的潜在替代品,用于研究被动透性和药物流量
Eva J Streekstra1, Marit Keuper-Navis2, Jeroen J M W van den Heuvel3
1Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen (Route 137), Nijmegen, the Netherlands; Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
概括
人体肠状单层显示出研究肠道药物吸收的前景,模仿排泄物运输和与新鲜组织相似的基因表达. 这种多功能模型补充了现有的体外方法,用于药物疗效和安全性评估.
科学领域:
- 药理学和药物输送 药理学和药物输送
- 胃肠病学 胃肠病学
- 生物技术是生物技术.
背景情况:
- 肠道对于口服药物吸收至关重要,影响生物可用性,疗效和安全性.
- 当前的体外试验模型往往无法准确地复制人类的肠道屏障和吸收过程.
- 准确的非临床模型对于预测体内药物行为至关重要.
研究的目的:
- 为了评估人类肠单层作为肠道药物吸收研究的模型.
- 为了比较体单层与初级肠组织 (Ussing腔) 和Caco-2细胞.
- 评估体对研究毒品运输机制和区域特异性的适用性.
主要方法:
- 双向药物运输测定使用肠状单层,新鲜的肠道组织和Caco-2细胞进行.
- 显而易见的透性 (Papp) 和外流比率被确定为近细胞 (enalaprilat),跨细胞 (propranolol),P-糖蛋白 (P-gp) (talinolol) 和乳腺癌抗性蛋白 (BCRP) (罗斯瓦斯塔丁) 的基质.
- 大量RNA测序被用来比较体单层和初级组织之间的基因表达特征.
主要成果:
- 这三种模型都证明了功能性的P-gp和BCRP流量输送,其基底侧到顶峰 (B-to-A) 输送率高于顶峰到底侧 (A-to-B) 输送.
- 塔利诺洛尔和罗斯瓦斯塔丁的B-to-AP值在新鲜组织和体单层之间是可比的.
- 与新鲜组织相比,体单层表现出较低的细胞内纳拉普利拉酸运输和较高的跨细胞醇运输,以及更具区域特异性的基因表达.
结论:
- 人体肠单层有效地模仿肠道药物运输的关键方面,包括由P-gp和BCRP介导的活性流量.
- 体单层在复制人类肠道中发现的特定区域的基因表达模式方面表现有前途.
- 体单层是一种多功能和有前途的实验平台,可以增强当前的体外肠道吸收模型.
相关概念视频
01:16Methods for Studying Drug Absorption: In vitro
213
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...
213
01:09Methods for Studying Drug Absorption: In situ
216
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,...
216
01:06Carrier-Mediated Transport
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Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
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