| A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. | |
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MedLine Citation:
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PMID: 16685052 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: The American journal of clinical nutrition Volume: 83 ISSN: 0002-9165 ISO Abbreviation: Am. J. Clin. Nutr. Publication Date: 2006 May |
Date Detail:
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Created Date: 2006-05-10 Completed Date: 2006-06-20 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0376027 Medline TA: Am J Clin Nutr Country: United States |
Other Details:
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Languages: eng Pagination: 1097-105 Citation Subset: AIM; IM |
Affiliation:
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Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, NC, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult 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* Female Fruit / chemistry* Humans Intestines / ultrastructure Male Microsomes / enzymology Psoralens / analysis*, chemistry, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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GM-38149/GM/NIGMS NIH HHS; M01-RR-00046/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Psoralens; 72509-76-3/Felodipine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A |
| Comments/Corrections | |
Erratum In:
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Am J Clin Nutr. 2006 Jul;84(1):264 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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