Role of intestinal oxidative metabolism on first pass effect

免疫印迹法检测兔肠组织中CYP1A、CYP2C、CYP2D和CYP3A蛋白的表达，发现利福平诱导了CYP3A蛋白的表达。从葡萄柚汁中分离到5个抑制人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强候选病原体。在培养液中加入葡萄柚汁乙酸乙酯提取物，导致CYP3A4、CYP1A2、CYP2C9、CYP2C19和CYP2D6的活性降低。呋喃香豆素明显抑制CYP3A4催化的硝苯地平氧化，呈剂量和时间依赖性，表明这些化合物是基于机制的CYP3A4抑制剂。在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体内奥美拉唑代谢的影响，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（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（肝脏特异性表达CYP2C 19活性指数）在两个实验中没有差异。这些数据表明，西柚汁的作用可能局限于胃肠道，而不会扩展到肝脏p450。

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.