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To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects.A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing.The plasma concentrations of (S)-manidipine were significantly higher (P< 0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC0–∞ of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased Cmax and AUC0–∞ of (S)-manidipine by 2.4-fold (P< 0.01) and 2.3-fold (P< 0.01), respectively, and Cmax and AUC0–∞ of (R)-manidipine were increased by 3.4-fold (P< 0.01) and 3.0-fold (P< 0.01), respectively. There were significant differences (P< 0.01) in GFJ-mediated percentage increases in Cmax and AUC0–∞ of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC0–∞ was significantly decreased from 1.6 to 1.2 during the GFJ phase (P< 0.01).These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine.