Objective: To test whether naringin or 6',7'-dihydroxybergamottin is a major active substance in grapefruit 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 responsible for inhibition of cytochrome P450 3A4 in humans.