放出和吸收的运输和肠道微生物的raloxifene糖酸的重新激活
Arttu Uoti1,2, Mika Kurkela3,4, Mikko Niemi3,4,5
1Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Basic & clinical pharmacology & toxicology
|December 20, 2024
概括
拉洛西芬葡萄化物由特定的载体运输,并被肠道微生物分解. 这解释了一些患者的拉洛西芬药物水平的变化.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药物新陈代谢 药物新陈代谢
- 胃肠病学 胃肠病学
背景情况:
- 拉洛西芬具有较低的生物可用性和高的药理动力学变异性.
- 由运输体和肠道微生物活动影响的肠肝循环有助于这种变异性.
- 缺乏对拉洛西芬处置途径的详细描述.
研究的目的:
- 为了研究拉洛西芬及其葡萄糖化物代谢物与药物载体的相互作用.
- 为了评估人类肠道微生物群对拉洛西芬葡萄糖化物的脱葡萄糖化.
- 阐明拉洛西芬的药理动力学变异性背后的机制.
主要方法:
- 利用Sf9膜囊泡和HEK293细胞研究载体相互作用.
- 评估了主要药物运输商运输的拉洛西芬及其葡萄化物 (4'-葡萄化物,6 - 葡萄化物,4',6 - 葡萄化物).
- 测量了人类便提取物中的拉洛西芬糖酸的脱糖化活性.
主要成果:
- 拉洛西芬葡萄化物是多重耐药性相关蛋白质 (MRP2和MRP3) 的基质.
- 拉洛西芬单糖化物被确定为有机离子载体聚的基质 (OATP1B1,OATP1B3和OATP2B1).
- 所有测试的拉洛西芬糖化物都经历了肠道微生物酶的显著降糖化,显示出高度的个体间差异.
结论:
- 拉洛西芬的排放受到运输媒介过程和肠道微生物代谢的显著影响.
- 已确定的输送物相互作用和微生物脱糖化途径有助于拉洛西芬的肠肝循环.
- 这些发现更深入地了解了拉洛西芬药理动学的个体间变异的来源.
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