Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects

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Abstract
Aim: To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects.Methods: 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.Results: 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).Conclusion: 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.

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