类药物用于研究儿科肠道药物运输
Eva J Streekstra1,2, Marit Keuper-Navis2,3, Jeroen J M W van den Heuvel1
1Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
Molecular pharmaceutics
|September 16, 2024
概括
儿科体精确地模拟了肠道药物运输和基因表达,显示与年龄相关的药物动力学差异,类似于人类组织. 这证实了体作为一个有前途的体外工具,用于儿科药物开发.
科学领域:
- 药理动力学和药物新陈代谢
- 胃肠病学和肝病学
- 儿科药理学 儿科药理学
背景情况:
- 产后的肠道成熟显著改变了药物的药理动力学 (PK),影响了儿科药物的安全性和有效性.
- 对于在发育中的儿科肠道中与本体发生相关的PK模式的理解有限.
- 人体肠状单层为研究儿科肠道药物运输提供了一个潜在的体外模型.
研究的目的:
- 为了评估人类肠单层的准确性,用于研究小儿肠道中的药物运输.
- 为了比较儿科和成人肠膜单层与肠组织中的药物输送器功能和基因表达.
- 用体模型研究药物运输和代谢与年龄相关的变化.
主要方法:
- 来自儿科和成人捐赠者的培养性肠单层.
- 进行了双向药物运输实验,使用埃纳拉普利拉特,普拉诺洛尔,塔利诺洛尔和罗斯瓦斯塔丁.
- 分析了药物载体表达 (P-gp,BCRP) 和ADME相关的基因模式,通过RNA测序在体和组织扩展物 (Ussing室).
主要成果:
- 通过P-gp和BCRP进行的流动输送在体和组织之间是可比的.
- RNA测序揭示了新生儿和成年人之间的药物代谢中与年龄相关的变化,无论是体和组织.
- 药物运输在体中通常与ex vivo组织实验保持一致,支持体作为有效的模型.
结论:
- 儿科内类单层显示了与肠道组织相似的药物载体功能和基因表达模式.
- 类药物有效地模拟了体内观察到的与年龄相关的药物动力学差异,特别是在新生儿和成年人之间.
- 人类儿科肠体代表了一个有价值和多功能的体外平台,用于调查儿科药物运输和发育变化.
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...
210
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,...
213
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...
313
01:14Hepatic Drug Clearance: Role of Transporters
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In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
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01:23Mechanisms of Drug Absorption: Paracellular, Transcellular, and Vesicular Transport
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Drugs need to permeate cell membranes to reach their target sites after administration. Orally administered drugs must transcend intestinal epithelial membrane barriers to infiltrate the systemic circulation. Drugs with a molecular weight of less than 500 Daltons diffuse through gaps between neighboring cells, called paracellular pathways.
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However, most drugs use the transcellular route, traversing directly through the cell membranes via two mechanisms: passive and active transport. Passive...
469
01:18Drug Delivery: Enteral Route
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The enteral drug administration involves three primary routes: oral, sublingual, and buccal. Oral ingestion is the most prevalent, safe, economical, and convenient method for drug administration. However, it has certain drawbacks, including limited absorption due to the drug's low water solubility or poor membrane permeability, possible emesis from GI mucosa irritation, destruction of drugs by digestive enzymes or low gastric pH, and irregular absorption along with food or other drugs.
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