Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.
OBJECTIVE
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.
Lilja
Jari J
JJ
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. jari.lilja@hus.fi
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D002957:Citrus; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C063287:simvastatin acid; D019821:Simvastatin