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Grapefruit juice—felodipine interaction: Effect of naringin and 6′,7′‐dihydroxybergamottin in humans
Author(s) -
Bailey David G.,
Kreeft John H.,
Munoz Claudio,
Freeman David J.,
Bend John R.
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90173-4
Subject(s) - felodipine , naringin , grapefruit juice , chemistry , cmax , chromatography , cmin , pharmacokinetics , food science , pharmacology , medicine , blood pressure , radiology
Objective To test whether naringin or 6′,7′‐dihydroxybergamottin is a major active substance in grape‐fruit juice‐felodipine interaction in humans. Methods Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6′,7′‐dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral felodipine were assessed in 12 healthy men in a randomized, 4‐way crossover study. Results The amounts of naringin and 6′,7′‐dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration‐time curve (AUC) and the peak concentration (C max ) of felodipine were higher with supernatant fraction (81 nmol · h/L and 20 nmol/L), particulate fraction (117 nmol · h/L and 24 nmol/L), and grapefruit juice (130 nmol · h/L and 33 nmol/L) compared with water (53 nmol · h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for felodipine and a similar C max of felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydrofelodipine nor decreased the AUC ratio of dehydrofelodipine to felodipine compared with water. Individually the supernatant fraction consistently produced lower felodipine AUC and C max compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction. Conclusions Naringin and 6′,7′‐dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice‐felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsibile for inhibition of cytochrome P450 3A4 in humans. Clinical Pharmacology & Therapeutics (1998) 64 , 248–256; doi:

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