Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients

Objectives: To determine whether unprocessed grapefruit can cause a drug in teraction, whether the active ingredients are naturally occurring, and whet her specific furanocoumarins or flavonoids are involved. Methods: The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extende d-release tablet with 250 mt commercial grapefruit juice, homogenized grape fruit segments, or extract of segment-free parts equivalent to one unproces sed fruit or mater in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) wa s determined. Furanocoumarin and naringenin precursor (naringin) concentrat ions were measured in each grapefruit treatment, Results: Felodipine AUC with commercial grapefruit juice, grapefruit segmen ts, or grapefruit extract was on average 3-fold higher than that with water . Felodipine peak concentration was higher, but the half-life was unchanged , The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumari ns produced mechanism-based and competitive inhibition of CYP3A4, Bergamott in was the most potent mechanism-based inhibitor. Naringenin isomers produc ed only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, an d naringin concentrations varied among grapefruit treatments but were suffi cient to inhibit markedly in vitro CYP3A4 activity. Conclusions: Unprocessed grapefruit can cause a drug interaction with felod ipine, The active ingredients are naturally occurring in the grapefruit. Be rgamottin is likely important in drug interactions with commercial grapefru it juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.