OBJECTIVE To assess relative roles of the intestinal and hepatic stereoselective metabolism of nicardipine in an oral first-pass disposal with and without grapefruit juice intake. METHODS The kinetic profiles of (+)- and (-)-nicardipine were studied in the six normal healthy male volunteers who received oral (40 mg) and intravenous (2 mg) racemic nicardipine, first with water and second with grapefruit juice. Both the enantiomers were determined by the stereoselective high-performance liquid chromatographic method, and hemodynamic parameters (arterial blood pressure, heart rate, and electrocardiogram) were assessed when each blood sample was taken. RESULTS Grapefruit juice compared with water intake caused a significant (P < 0.05) increase in the mean oral (+)- and (-)-nicardipine bioavailability (Fobs) (48.6+/-5.0% and 105.6+/-7.8%) and dose-absorbed (Fabs) available fraction unmetabolized at the gut (Fg) (48.2+/-5.6% and 110.9+/-8.8%, respectively) with no significant change in the hepatic first-pass effect. However, all of the mean kinetic parameters of both the enantiomers after the intravenous dosing of racemic nicardipine did not differ between the grapefruit juice- and water-intake trial phases. The mean percentage changes in oral AUC (43.1+/-3.4% in [+]-nicardipine and 90.9 6.4% in [-]-nicardipine, or Fobs) and Fabs Fg by grapefruit juice tended to be greater for (-)-nicardipine than for (+)-nicardipine and the mean oral (+)/(-)-nicardipine AUC ratio was significantly reduced by grapefruit juice (from 2.25+/-0.37 to 1.75+/-0.28) (P < 0.05). Except for heart rates, which were greater with grapefruit juice (P < 0.05) at 1 and 2 h after the oral dose of nicardipine, the mean hemodynamic variables did not differ between the two trial phases. CONCLUSIONS We conclude that the gut is the major presystemic disposal site of racemic nicardipine in humans. Grapefruit juice appears to affect this metabolic disposal of (-)-nicardipine to a somewhat greater extent compared with that of (+)-nicardipine, with an early postdose transient tachycardia after the oral dosing of racemic nicardipine.