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6',7'-Dihydroxybergamottin in Grapefruit Juice and Seville Orange Juice: Effects on Cyclosporine Disposition, Enterocyte CYP3A4, and P-glycoprotein

6',7'-Dihydroxybergamottin in Grapefruit Juice and Seville Orange Juice: Effects on Cyclosporine Disposition, Enterocyte CYP3A4, and P-glycoprotein

D J Edwards, M E Fitzsimmons, E G Schuetz, K Yasuda, M P Ducharme, L H Warbasse, P M Woster, J D Schuetz, P Watkins

Clin Pharmacol Ther. 1999 Mar;65(3):237-44.

PMID: 10096255

Abstract:

Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
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 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP145414762	6´,-7´-Dihydroxybergamottin		145414-76-2	Price

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