Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers

Abstract.

Objectives: To determine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of S- and R-verapamil (given as racemates) at steady state. Methods: Nine healthy male volunteers followed a randomised cross-over study comprising two treatment periods. Pretreatments of 200 ml orange juice (control) or grapefruit juice twice daily for 5 days and 120 mg verapamil (orally) twice daily for 3 days were given. On the study day, the subjects received the morning dose of verapamil with either orange juice (control) or grapefruit juice. Plasma and urine samples were collected for measurement of S- and R-verapamil and the metabolites S- and R-norverapamil. Blood pressure (BP), heart rate (HR) and PR-interval were monitored. Results: During the grapefruit juice period, the steady-state peak and trough concentrations of S-verapamil were moderately increased (peak 41±25 ng ml^–1 versus 26±13 ng ml^–1, trough 14±7 ng ml^–1 versus 12±6 ng ml^–1, P=0.08). Grapefruit juice significantly increased the area under the plasma concentration–time curve during the 12-h dose interval (AUC_0–12 h) of S-verapamil by 36% (292±146 ng h ml^–1 versus 215±102 ng h ml^–1, P=0.04). Similar results were obtained for peak and trough concentrations of R-verapamil. The AUC_0–12 h of R-verapamil was increased by 28% (1022±412 ng h ml^–1 versus 800±316 ng h ml^–1, P=0.04). Elimination half-life and renal clearance of both S- and R-verapamil were not affected. Considerable inter-subject variability in interaction was shown. There were no significant differences in the pharmacodynamic parameters (BP, HR and PR-interval). Conclusions: The present study has demonstrated an interaction between verapamil and grapefruit juice, which is likely due to an inhibition of intestinal metabolism resulting in increased oral bioavailability.