Grapefruit juice increases serum concentrations of atorvastatin and has noeffect on pravastatin

Background: Grapefruit juice greatly increases the bioavailability of lovas tatin and simvastatin. We studied the effect of grapefruit juice on the pha rmacokinetics of atorvastatin and pravastatin. Methods: Two randomized, two-phase crossover studies were performed-study I with atorvastatin in 12 healthy volunteers and study II with pravastatin i n 11 healthy volunteers. In both studies, volunteers took 200 mL, double-st rength grapefruit juice or water three times a day for 2 days. On day 3, ea ch subject ingested a single 40 mg dose of atorvastatin (study I) or pravas tatin. (study II) with either 200 mt grapefruit juice or water, and an addi tional 200 mt was ingested 1/2 hour and 1 1/2 hours later. In addition, sub jects took 200 mt grapefruit juice or water three times a day on days 4 and 5 in study I. In study I, serum concentrations of atorvastatin acid, atorv astatin lactone, 2-hydroxyatorvastatin acid, 2-hydroxyatorvastatin lactone, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc tase inhibitors were measured up to 72 hours. In study II, pravastatin, pra vastatin lactone, and active and total HMG-CoA reductase inhibitors were me asured up to 24 hours. Results: Grapefruit juice increased the area under the serum concentration- time curve of atorvastatin acid from time zero to 72 hours [AUC(0-72)] 2.5- fold (P <.01), whereas the peak serum concentration (C-max) was not signifi cantly changed. The time of the peak concentration (t(max)) and the elimina tion half-life (t(1/2)) of atorvastatin acid were increased (P <.01). The A UC(0-72) of atorvastatin lactone was increased 3.3-fold (P <.01) and the C- max 2.6-fold (P <.01) by grapefruit juice, and the t(max) and t(1/2) were a lso increased (P <.05). Grapefruit juice decreased the C-max (P <.001) and AUC(0-72) (P <.001) of 2-hydroxyatorvastatin acid and increased its t(max) and t(1/2) (P <.01). Grapefruit juice also decreased the C-max (P <.001) an d AUC(0-72) (P <.05) of 2-hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.3-fold ( P <.05) and 1.5-fold (P <.01), respectively, by grapefruit juice. In study II, the only significant change observed in the pharmacokinetics of pravast atin was prolongation of the t(max) of active HMG-CoA reductase inhibitors by grapefruit juice (P <.05). Conclusions: Grapefruit juice significantly increased serum concentrations of atorvastatin acid, atorvastatin lactone, and active and total HMG-CoA re ductase inhibitors, probably by decreasing CYP3A4-mediated first-pass metab olism of atorvastatin in the small intestine. On the other hand, grapefruit juice had no effect on the pharmacokinetics of pravastatin. Concomitant us e of atorvastatin and at least large amounts of grapefruit juice should be avoided, or the dose of atorvastatin should be reduced accordingly.