Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.

AIMS: Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. RESULTS: Grapefruit juice increased the area under the plasma concentration-time curves from 0 to 24 h [AUC(0-24)] of simvastatin 3.6-fold (range 1.8-6.0-fold; P < 0.01) and that of simvastatin acid 3.3-fold (range 2.1-5.6-fold; P < 0.01), respectively. The peak concentrations (C(max)) of simvastatin and simvastatin acid were increased 3.9-fold (range 2.3-9.3-fold; P < 0.01) and 4.3-fold (range 2.7-7.9-fold; P < 0.01) by grapefruit juice. CONCLUSIONS: Even one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol-lowering effect and the risk of adverse effects of simvastatin.