Role of intestinal oxidative metabolism on first pass effect

肠道氧化代谢对首过效应的作用

基本信息

批准号：
09470496
负责人：
YAMAZOE Yasushi
金额：
$ 4.93万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

In rabbit Intestine, the expression of CYP1A, CYP2C, CYP2D and CYP3A proteins was detected by immuno blot analyses, and CYP3A forms were found to be induced by rifampicin.Five components were isolated from grapefruit juice that inhibit human CYP3A-mediated drug oxidation. They include two furocoumarin dimers (GF-I-1 and GF-I-4) which are strong candi-dates for causative agents of grapefruit juice-mediated drug interaction.Addition of ethyl acetate extract of grapefruit juice Into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, CYP2C19 and CYP2D6. The furocoumarins clearly Inhibited CYP3A4-catalyzed nifedipine oxidation in dose- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furocoumarin investigated, furocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4.To determine the effect of grapefruit juice on omeprazole metabolism in vivo, omeprazole was taken orally by 13 healthy volunteers. AUC ratio of omeprazole sulfone to omeprazole, index of CYP3A4 activity, was decreased 33% (p< 0.001) by grapefruit juice intake whereas AUC ratio of 5-hydroxyomeprazole to omeprazole, index of liver-specific expressed CYP2C 19 activity, did not differ between two experiments. These data suggest that effect of grapefruit juice may confine within gastrointestinal tract, and not extend to hepatic P450s.

通过免疫印迹分析检测兔小肠中CYP1A、CYP2C、CYP2D和CYP3A蛋白的表达，并发现利福平诱导CYP3A形式。从柚子汁中分离出五种抑制人CYP3A介导的药物氧化的成分。它们包括两种呋喃香豆素二聚体（GF-I-1 和 GF-I-4），它们是葡萄柚汁介导的药物相互作用的致病因子的有力候选者。将葡萄柚汁的乙酸乙酯提取物添加到孵育混合物中导致减少CYP3A4、CYP1A2、CYP2C9、CYP2C19 和 CYP2D6 的活性。呋喃香豆素以剂量和时间依赖性方式明显抑制 CYP3A4 催化的硝苯地平氧化，表明这些化合物是基于机制的 CYP3A4 抑制剂。在所研究的呋喃香豆素中，呋喃香豆素二聚体 GF-I-1 和 GF-I-4 是 CYP3A4 最有效的抑制剂。为了确定葡萄柚汁对奥美拉唑体内代谢的影响，13 名健康志愿者口服奥美拉唑。摄入葡萄柚汁后，奥美拉唑砜与奥美拉唑的 AUC 比率（CYP3A4 活性指数）降低了 33%（p < 0.001），而 5-羟基奥美拉唑与奥美拉唑的 AUC 比率（肝脏特异性表达的 CYP2C 19 活性指数）在两组之间没有差异。两个实验。这些数据表明，柚子汁的作用可能仅限于胃肠道内，而不会延伸至肝脏 P450。