Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/24/2006
Publication Date: 5/1/2006
Citation: Paine, M.F., Widmer, W.W., Pusek, S.N., Beavers, K.L., Criss, A.B., Brown, S.S., Thomas, B.F., Watkins, P.B. 2006. A "furanocoumarin-free" grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. American Journal of Clinical Nutrition. 83:1097-1105. Interpretive Summary: Grapefruit juice (GFJ) enhances the absorption of certain prescription drugs, including felodipine, that are metabolized by intestinal CYP3A4 enzyme by inhibiting enzyme activity. Furanocoumarins have been identified as the major CYP3A4 inhibitors contained in the juice, but their contribution to the “grapefruit juice effect” in vivo remains unclear. In order to determine the extent to which furanocoumarins contribute to the inhibitory effect on CYP3A4 enzyme caused by grapefruit juice, a “furanocoumarin-free” (FC-free) GFJ was created using food grade solvents and absorption resins where greater than 98% of the furanocoumarins were removed while the other major major ingredients (flavonoids) were retained. The FC-free GFJ was tested against orange juice as a control and the original GFJ using on the oral pharmacokinetics of felodipine, and an open three-way randomized crossover design with 18 healthy volunteers. For the trial, 10 mg felodipine was ingested with a 240 mL (8 oz) serving using one of the three juices, and blood samples were collected over 24 hours. Each subject ingested all 3 juices with at least one week having elapsed between each juice treatment for an individual. In each subject, relative to OJ, only the original GFJ and not the FC-free GFJ increased felodipine systemic exposure. From this it can be concluded that the furanocoumarins which were removed are the active ingredients responsible for enhancing the systemic exposure of felodipine and probably other medications that are metabolized by intestinal CYP3A4 enzyme and undergo extensive intestinal first-pass metabolism.
Technical Abstract: Background: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as the major CYP3A4 inhibitors contained in the juice, but their contribution to the “grapefruit juice effect” in vivo remains unclear. Objective: To determine whether furanocoumarins mediate the GFJ-felodipine interaction, a “furanocoumarin-free” (FC-free) GFJ was created and tested against orange juice (OJ) (control) and the original GFJ on the oral pharmacokinetics of felodipine. Design: Using food-grade solvents and absorption resins, furanocoumarins were removed (>98%) from whole GFJ, while other major ingredients (flavonoids) were retained. By open, three-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with one of the three juices (240 mL). Blood was collected over 24 hours. At least one week elapsed between juice treatments. Results: In each subject, relative to OJ, only GFJ increased felodipine systemic exposure. GFJ significantly increased the median AUC (110 nmol/L-h) and Cmax (21 nmol/L) relative to both OJ (54 nmol/L-h and 7.6 nmol/L, respectively) and FC-free GFJ (48 nmol/L-h and 8.3 nmol/L, respectively) (P < 0.001). Neither the median Tmax (2.5 vs. 2.8 vs. 2.5 h) nor terminal t1/2 (6.6 vs. 7.8 vs. 6.8 h) differed among the three juices (GFJ vs. OJ vs. FC-free GFJ) (P > 0.09). Conclusion: Furanocoumarins are the active ingredients responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism