GRAPEFRUIT JUICE FELODIPINE INTERACTION - MECHANISM, PREDICTABILITY, AND EFFECT OF NARINGIN

Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single pr imary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in wa ter at the same concentration as the juice in a randomized crossover t rial of nine healthy men. With grapefruit juice, mean +/- SEM felodipi ne area under the plasma concentration-time curve (AUC) and peak plasm a concentration (C(max)) were 206% +/- 23% (range, 123% to 330%, p < 0 .01) and 170% +/- 24% (range, 127% to 310%, p < 0.02), respectively, c ompared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 /- 0.2 versus 2.2 +/- 0.2, p < 0.001) and felodipine C(max) (1.5 +/- 0 .2 versus 2.2 +/- 0.2, p < 0.001) were reduced, consistent with inhibi tion of presystemic felodipine metabolism. Intersubject changes in fel odipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could n ot be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other fact ors were important.