Document Detail

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.
MedLine Citation:
PMID:  16685052     Owner:  NLM     Status:  MEDLINE    
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 major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear. OBJECTIVE: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine. DESIGN: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximately 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments. RESULTS: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol . h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol . h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol . h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively]. CONCLUSION: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.
Mary F Paine; Wilbur W Widmer; Heather L Hart; Susan N Pusek; Kimberly L Beavers; Anne B Criss; Sherri S Brown; Brian F Thomas; Paul B Watkins
Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The American journal of clinical nutrition     Volume:  83     ISSN:  0002-9165     ISO Abbreviation:  Am. J. Clin. Nutr.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-05-10     Completed Date:  2006-06-20     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376027     Medline TA:  Am J Clin Nutr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1097-105     Citation Subset:  AIM; IM    
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, NC, USA.
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MeSH Terms
Beverages / analysis*
Caco-2 Cells
Citrus paradisi / chemistry*
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System / antagonists & inhibitors
Drug Interactions
Enzyme Inhibitors
Felodipine / blood,  pharmacokinetics*
Fruit / chemistry*
Intestines / ultrastructure
Microsomes / enzymology
Psoralens / analysis*,  chemistry,  pharmacology*
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Psoralens; 72509-76-3/Felodipine; 9035-51-2/Cytochrome P-450 Enzyme System; EC protein, human; EC P-450 CYP3A
Erratum In:
Am J Clin Nutr. 2006 Jul;84(1):264

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