Edwards D J, Fitzsimmons M E, Schuetz E G, Yasuda K, Ducharme M P, Warbasse L H, Woster P M, Schuetz J D, Watkins P
College of Pharmacy and School of Medicine, Wayne State University, Detroit, Mich, USA.
Clin Pharmacol Ther. 1999 Mar;65(3):237-44. doi: 10.1016/S0009-9236(99)70102-5.
6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CYP3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, including cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability.
To evaluate the contribution of 6',7'-dihydroxybergamottin to the effects of grapefruit juice on cyclosporine disposition and to assess the role of CYP3A4 versus P-glycoprotein in this interaction.
The disposition of oral cyclosporine was compared in healthy subjects after ingestion of water, grapefruit juice, and Seville orange juice. Enterocyte concentrations of CYP3A4 were measured in 2 individuals before and after treatment with Seville orange juice. The effect of 6',7'-dihydroxybergamottin on P-glycoprotein was assessed in vitro.
Area under the whole blood concentration-time curve and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6',7'-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 micromol/L.
6',7'-Dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte concentrations of CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P-glycoprotein.
6',7'-二羟基香豆素是一种呋喃香豆素，可抑制CYP3A4，存在于葡萄柚汁和酸橙汁中。葡萄柚汁可提高许多CYP3A4底物的口服生物利用度，包括环孢素（国际非专利药品名称，环孢菌素），但肠道P-糖蛋白可能是环孢素生物利用度更重要的决定因素。
评估6',7'-二羟基香豆素对葡萄柚汁中环孢素处置效应的贡献，并评估CYP3A4与P-糖蛋白在这种相互作用中的作用。
在健康受试者摄入水、葡萄柚汁和酸橙汁后，比较口服环孢素的处置情况。在2名个体接受酸橙汁治疗前后，测量肠细胞中CYP3A4的浓度。在体外评估6',7'-二羟基香豆素对P-糖蛋白的影响。
葡萄柚汁使环孢素的全血浓度-时间曲线下面积和峰值浓度分别增加了55%和35%（P <.05）。酸橙汁对环孢素处置没有影响，但使肠细胞中CYP3A4的浓度平均降低了40%。在浓度高达50 μmol/L时，6',7'-二羟基香豆素不抑制P-糖蛋白。
6',7'-二羟基香豆素对葡萄柚汁中环孢素的影响无作用。尽管肠细胞中CYP3A4的浓度降低，但酸橙汁未发生这种相互作用，可能是葡萄柚汁中的其他化合物抑制了P-糖蛋白活性。6',7'-二羟基香豆素使肠细胞CYP3A4减少，对于生物利用度较少依赖P-糖蛋白的其他药物可能很重要。
