Grapefruit juice-felodipine interaction: Effect of naringin and 6′,7′-dihydroxybergamottin in humans

• Published in: Clinical pharmacology and therapeutics 1998-09, Vol.64 (3), p.248-256
• Main Authors: Bailey, David G., Kreeft, John H., Munoz, Claudio, Freeman, David J., Bend, John R.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Anti-Arrhythmia Agents - blood; Anti-Arrhythmia Agents - pharmacokinetics; Antihypertensive agents; Antioxidants - pharmacology; Area Under Curve; Beverages; Biological and medical sciences; Biological Availability; Calcium Channel Blockers - blood; Calcium Channel Blockers - pharmacokinetics; Cardiovascular system; Citrus - metabolism; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Felodipine - blood; Felodipine - pharmacokinetics; Flavanones; Flavonoids - pharmacology; Food-Drug Interactions; Furocoumarins - pharmacology; Humans; Male; Medical sciences; Mixed Function Oxygenases - antagonists & inhibitors; Pharmacology. Drug treatments; Reference Values
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(98)90173-4

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 (Cmax) 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 Cmax 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 Cmax 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: