Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.
BACKGROUND
Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of grapefruit juice with lovastatin, a cholesterol-lowering agent that is partially metabolized by CY P3A4.


METHODS
An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml grapefruit juice or water, and an additional dose of 200 ml was ingested 1/2 and 1 1/2 hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours.


RESULTS
Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0-12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by grapefruit juice. The mean Cmax and AUC(0-12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged.


CONCLUSIONS
Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.
Kantola
T
T
Department of Clinical Pharmacology, University of Helsinki, Finland.
Kivistö
K T
KT
Neuvonen
P J
PJ
D000143:Acids / Q000097:blood; D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D002957:Citrus; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood*; D008148:Lovastatin / Q000097:blood*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012016:Reference Values
D000143:Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human