Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers

Objectives: Grapefruit juice has been reported to increase the bioavailability of several calcium-channel antagonists, i.e. the dihydropyridines and verapamil, which are cytochrome P-450 3A4 (CYP3A4) substrates. The objective of the present study was to investigate the effect of grapefruit juice on the pharmacokinetics of diltiazem and the metabolites N-demethyl-diltiazem (MA) and desacetyl-diltiazem (M1). Methods: Ten healthy male volunteers were included in a randomised, open, crossover study, comparing the effect of a single oral dose of non-retard formulated diltiazem (120 mg) administered with 250 ml grapefruit juice or water. The study was performed on two investigation days separated by 13-38 days (median 28 days). Plasma samples were collected for measurement of diltiazem and the metabolites MA and M1. Blood pressure and heart rate were monitored throughout the study. Results: Grapefruit juice intake resulted in a statistically significant average individual increase in the area under the plasma diltiazem concentration-time curve (AUC(0-24)) of 20 +/- 25% (P = 0.02) compared with water. The average individual increase in peak plasma concentration (C-max) of diltiazem after grapefruit juice administration was 22 +/- 37%, but this effect was not statistically significant (P = 0.14). The time to C-max (t(max)) or terminal half-life was not affected by grapefruit juice. Considerable inter-individual variability in the interaction was observe There were no statistically significant differences in blood-pressure and heart rate between the two treatments. Conclusion: The present study demonstrated that a single intake of grapefruit juice (250 ml) caused a slight but statistically significant increase in the systemic exposure of diltiazem. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport may be responsible for this effect.