¹College of Pharmacy and School of Medicine, Wayne State University, Detroit; the Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada; the Department of Pharmaceutical Sciences, St Jude Children's Hospital, Memphis, Tenn; and the Department of Internal Medicine, University of Michigan, Ann Arbor, Mich

Correspondence: Paul Watkins, MD, University of Michigan Medical Center, Room A7119 University Hospital, Box 0108, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0108. Email: pwatkins@umich.edu

^*Supported in part by EHS Center grant 1-P30-ES06639 from the National Institute of Environmental Health Sciences (Dr Edwards), National Institutes of Health research grants ES05851 (Dr J.D. Schuetz), ES08658 (Dr E.G. Schuetz), and P30 CA21765 (Drs E.G. Schuetz and J.D. Schuetz), American Lebanese Syrian Associated Charities (Drs E.G. Schuetz and J.D. Schuetz), and NIGMS 38149 (Dr Watkins) and M01-RR-00042 (University of Michigan General Clinical Research Center).

Received 5 August 1998; Accepted 9 November 1998.

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 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 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.