A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction
A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction
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DOI：
10.1093/ajcn/83.5.1097
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发表时间：
2006-05-01
影响因子：
7.1
通讯作者：
Watkins, Paul B.
中科院分区：
文献类型：
--
作者：
Paine, Mary F.;Widmer, Wilbur W.;Watkins, Paul B.
背景资料：葡萄柚汁（GFJ）通过抑制肠道（而非肝脏）首过代谢，增强了许多CYP 3A 4药物底物（包括非洛地平）的全身暴露。呋喃香豆素已被确定为果汁中含有的主要CYP 3A 4抑制剂，但它们对体内GFJ效应的贡献仍不清楚。目的：为了确定呋喃香豆素是否介导GFJ与非洛地平的相互作用，制备了不含呋喃香豆素的GFJ，并针对橙子汁和原始GFJ进行了非洛地平口服药代动力学测试。设计：随着食品级溶剂和吸附树脂的使用，呋喃香豆素被删除（约99%）从整个GFJ，而其他主要成分（类黄酮）被保留。在一项开放、3向、随机交叉设计中，18名健康志愿者将非洛地平（10 mg）与3种果汁中的1种（240 mL）一起摄入。在24小时内收集血液。结果：非洛地平的曲线下面积和最大浓度的中位数和范围随着GFJ [110（范围：58-270）nmol（.）h/L和21（7.6-50）nmol/L]比橙子汁[54（29-150）nmol/L]低。h/L和7.6（3.4-13.9）nmol/L]或无呋喃香豆素GFJ [48（23-120）nmol（.）h/L和8.3（3.0-16.6）nmol/L]。GFJ、橙子汁和不含呋喃香豆素的GFJ没有显著差异（P > 0.09）达到最大血药浓度的中位时间[2.5（1.5-6）、2.8（1.5-4）和2.5（2-6）h]或终末半衰期[6.6（4.2-13.6）、7.8（4.4-13.2）和6.8（2.6-14.4）h]。呋喃香豆素类是GFJ中的活性成分，负责增强非洛地平的全身暴露，可能还有其他CYP 3A 4底物，肠道首过代谢
Background: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furano-coumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear.Objective: To ascertain whether furano-coumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine.Design: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximate to 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments.Results: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol (.) h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol (.) h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol (.) h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively].Conclusion: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.