6 ',7 '-Dihydroxybergamottin in grapefruit juice and Seville orange juice:Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein

Background: 6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CY P3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, includi ng cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability. Objectives: To evaluate the contribution of 6',7'-dihydroxybergamottin to t he effects of grapefruit juice on cyclosporine disposition and to assess th e role of CYP3A4 versus P-glycoprotein in this interaction. Methods: The disposition of oral cyclosporine was compared in healthy subje cts after ingestion of water, grapefruit juice, and Seville orange juice. E nterocyte concentrations of CYP3A4 were measured in 2 individuals before an d after treatment with Seville orange juice. The effect of 6',7'-dihydroxyb ergamottin on P-glycoprotein was assessed in vitro. Results: Area under the whole blood concentration-time curve and peak conce ntration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclos porine disposition but reduced enterocyte concentrations of CYP3A4 by an av erage of 40%. 6',7'-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 mu mol/L, Conclusions: 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 CYP3 A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxyberga mottin could be important for other drugs whose bioavailability is less dep endent on P-glycoprotein.