The interaction effect of grapefruit juice is maximal after the first glass

To compare the acute effect of grapefruit juice intake on the pharmacokinetics and haemodynamic effects of felodipine ER tablets with the interaction after 14 days intake of drug with juice.

Twelve healthy male volunteers were included in this cross-over trial and randomly allocated to a daily intake of a 10-mg felodipine extended release tablet with water or grapefruit juice for 14 days. The two study periods were separated by at least 14 days. The pharmacokinetics of felodipine and dehydrofelodipine, as well as the haemodynamic effects of the drug, were studied during day 1 and 14 in each period.

Similarly to previous single-dose studies, the treatment during the first day with grapefruit juice increased the AUC (+73%) and Cmax (+138%) of felodipine when compared with the control treatment. On day 14 a similar effect of grapefruit juice was observed, with an increased AUC24 (+57%) and Cmax (+114%) of felodipine compared with the control experiment. A significant accumulation of felodipine occurred during both the control (+37%) and grapefruit juice (+25%) period. The extent of accumulation was not significantly different in the two treatment periods. The pharmacokinetics of the metabolite dehydrofelodipine were affected to a similar extent by the juice on day 1 and day 14. The first dose of felodipine together with grapefruit juice was associated with a significant additional increase in heart rate when compared with the control therapy, whereas there was no additional effect on blood pressure when therapy included grapefruit juice. On day 14 the intake of drug with juice resulted in an additional increase in heart rate and reduction in diastolic blood pressure in comparison with the control experiment. Furthermore, the vascularly related adverse events were more frequent in the period including grapefruit juice.

The interaction between grapefruit juice and felodipine appears to be already fully developed after the first glass of grapefruit juice, as the change in pharmacokinetics in comparison with the control experiment is similar on day 1 and on day 14. Concomitant intake of 10 mg felodipine ER and the juice is associated with increased haemodynamic effects in healthy subjects both after a single dose and following 14 days of concomitant intake.