Role of intestinal oxidative metabolism on first pass effect

免疫印迹法检测兔肠道细胞色素P450 1 A、细胞色素P2 2 C、细胞色素P2 2 D和细胞色素P3 A蛋白的表达，发现利福平可诱导细胞色素P3 A的形成。它们包括两个呋喃香豆素二聚体(GF-I-1和GF-I-4)，这两个二聚体对西柚汁介导的药物相互作用的致病剂具有很强的耐受性。将西柚汁的乙酸乙酯提取物添加到孵化混合物中会导致细胞色素P3A4、细胞色素P1A2、细胞色素P450 2C9、细胞色素P450 2C19和细胞色素P450 2D6活性降低。呋喃香豆素类化合物以剂量和时间依赖的方式明显抑制CYP3A4催化的硝苯地平氧化，提示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对细胞色素P3A4的抑制作用最强。为了确定西柚汁对奥美拉唑体内代谢的影响，13名健康志愿者口服了奥美拉唑。摄入西柚汁后，反映细胞色素P3A4活性的指标奥美拉唑/奥美拉唑的AUC值降低了33%(p<0.001)，而肝脏特异性表达细胞色素P4C19活性的指标5-羟基奥美拉唑/奥美拉唑的AUC值在两次实验中无明显差异。这些数据表明，西柚汁的作用可能局限于胃肠道，而不是延伸到肝脏的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.