特定于年龄的ADME基因表达在婴儿肠道内中
Eva J Streekstra1,2, Tom Scheer-Weijers1, Michael Bscheider3
1Department of Pharmacy, Division of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
Molecular pharmaceutics
|August 9, 2024
概括
从婴儿组织培养的儿科肠杆菌维持药物输送器和酶基因表达模式. 这支持它们用于预测儿科药物安全性和优化剂量方案.
科学领域:
- 药理学和毒理学 药理学和毒理学
- 发展生物学 发展生物学
- 胃肠病学 胃肠病学
背景情况:
- 儿童吸毒倾向受到发育变化和环境因素的重大影响.
- 优化儿科药物剂量需要了解年龄相关的药物吸收,分布,新陈代谢和分泌 (ADME) 生物学.
- 现有的模型往往缺乏准确的儿科药物开发所需的特定年龄代表性.
研究的目的:
- 从婴儿肠道组织中建立和描述特定年龄的肠状细胞培养物.
- 研究这些体中关键的药物载体和代谢酶的表达.
- 评估儿科内类药物的潜力,作为预测儿童药物行为的模型.
主要方法:
- 从新鲜的婴儿 (n=8) 和成年人 (n=3) 肠道组织中培养出3D自我组织的体.
- 通过RT-qPCR确定药物载体 (P-gp,BCRP,MRP2,PEPT1) 和代谢酶 (CYP3A4,CYP2C18,UGT1A1) 的基因表达.
- 将体与原始组织的基因表达进行比较,并在体通道中评估稳定性.
主要成果:
- 类药物成功地重复了原生组织中发现的关键ADME基因的基因表达模式.
- P-gp,BCRP,MRP2和CYP3A4的表达水平在组织和体之间是相似的.
- 对几个关键基因观察到类似的成熟模式,表明生物相关性得到保留.
结论:
- 儿科体保持了临床相关ADME基因的成熟模式,反映了本地组织.
- 这些发现代表了在药物开发中利用儿科体来改善安全预测的重要一步.
- 儿科内类药物为儿童群体中药物暴露和肠道安全的特定年龄研究提供了一个有前途的平台.
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