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.

在兔肠中，通过免疫印迹分析检测到CYP1A，CYP2C，CYP2D和CYP3A蛋白的表达，发现CYP3A形式是通过利福平诱导的。从葡萄糖汁中分离出了five成分，从而抑制了抑制人类CYP3A人类CYP3A人类CYP3A介导的药物氧化的葡萄汁。它们包括两个Furocoumarin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剂的较强念珠菌。 Furocoumarins清楚地抑制了CYP3A4催化的硝苯地平的氧化和时间依赖性的方式，这表明这些化合物是基于机制的CYP3A4的抑制剂。在所研究的呋喃蛋白酶中，Furocoumarin二聚体GF-I-1和GF-I-4是CYP3A4的最有效抑制剂。确定葡萄柚汁对Omeprazole代谢对体内的影响，Omeprazole被13位健康志愿者口服服用。葡萄柚汁的摄入量降低了33％（P <0.001）的Omeprazole磺酮与Omeprazole的AUC比率降低了33％（P <0.001），而5-羟基蛋白酶与奥美拉唑的AUC比率降低了Omeprazole与Omerprazole的AUC比率，肝脏特异性表达的CYP2C 19活性在两种实验之间并没有不同。这些数据表明，葡萄柚汁的作用可能局限于胃肠道内，而不会扩展到肝P450。