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

Abstract

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 interindividual variability in the interaction was observed. 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.