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Title: Further characterization of a furanocoumarin-free grapefruit juice drug disposition: Studies with cyclosporine

Author
item PAINE, MARY - UNIV OF NORTH CAROLINA
item Widmer, Wilbur
item PUSEK, SUSAN - UNIV OF NORTH CAROLINA
item BEAVERS, KIMBERLY - UNIV OF NORTH CAROLINA
item CRISS, ANNE - UNIV OF NORTH CAROLINA
item SNYDER, JENNIFER - UNIV OF NORTH CAROLINA
item WATKINS, PAUL - UNIV OF NORTH CAROLINA

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/13/2008
Publication Date: 4/1/2008
Citation: Paine, M.F., Widmer, W.W., Pusek, S.N., Beavers, K.L., Criss, A.B., Snyder, J., Watkins, P.B. 2008. Further characterization of a furanocoumarin-free grapefruit juice drug disposition: Studies with cyclosporine. American Journal of Clinical Nutrition. 87:863-871.

Interpretive Summary: Grapefruit juice (GFJ) can increase the absorption of certain drugs by inhibiting an intestinal enzyme naturally present in the human intestine which deactivates a portion before they can be absorbed. We recently established furanocoumarins as the mediators of the interaction between GFJ and felodipine, one drug that is affected, using a “furanocoumarin-free” (FC-free) GFJ. Because the juice from Seville sour orange, which contains several of the major furanocoumarins as GFJ, produced an interaction with felodipine but not cyclosporine, we hypothesized that the FC-free GFJ might not remove the interaction potential with cyclosporine. After comparing absorption of cyclosporine in individuals following consumption of orange juice, GFJ, and the FC-Free GFJ, GFJ was found to significantly affect cyclosporine absorption compared to the orange juice control while the FC-free GFT did not. This led to the conclusions that furanocoumarins also mediate the GFJ-cyclosporine interaction, with the most plausible mechanism involving the combined inhibition of enteric CYP3A4 and P-gp. It also seems prudent to repeat the Seville OJ-cyclosporine interaction with a larger sample size.

Technical Abstract: Background: Grapefruit juice (GFJ) can increase drug systemic exposure by inhibiting intestinal CYP3A4-mediated first-pass metabolism. We recently established furanocoumarins as the mediators of the interaction between GFJ and felodipine, a substrate for CYP3A4 but not P-gp, using a “furanocoumarin-free” (FC-free) GFJ. Previous studies with Seville orange juice, which contains several of the major furanocoumarins as GFJ, produced an interaction with felodipine but not cyclosporine, a dual CYP3A4/P-gp substrate. Accordingly, we hypothesized that the FC-free GFJ would not remove the interaction potential with cyclosporine. Methods: By randomized crossover design, cyclosporine (5 mg/kg) was given to 18 healthy volunteers with 240 ml of orange juice (OJ) (control), whole GFJ, or FC-free GFJ. Blood was collected over 24 hours. Each juice treatment was separated by at least one week. Results: Compared to OJ, GFJ significantly increased the median AUC (3.9 vs. 5.5 mg/L-hr) and Cmax (0.81 vs. 1.05 mg/L) and decreased the median Cl/F (89 vs. 64 L/hr) (P ' 0.007) of cyclosporine. In contrast, FC-free GFJ did not alter these outcomes (4.6 mg/L-h, 0.87 mg/L, and 88 L/h, respectively) (P ' 0.50). Both the median terminal Tmax and t1/2 were similar among the three juices (2-3 h and 7-8 h, respectively) (P ' 0.08). Conclusions: Furanocoumarins mediate the GFJ-cyclosporine interaction, with the most plausible mechanism involving the combined inhibition of enteric CYP3A4 and P-gp. It also seems prudent to repeat the Seville OJ-cyclosporine interaction with a larger sample size.