Lilja J J, Kivistö K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Clin Pharmacol Ther. 1999 Aug;66(2):118-27. doi: 10.1053/cp.1999.v66.100453001.
Grapefruit juice greatly increases the bioavailability of lovastatin and simvastatin. We studied the effect of grapefruit juice on the pharmacokinetics of atorvastatin and pravastatin.
Two randomized, two-phase crossover studies were performed--study I with atorvastatin in 12 healthy volunteers and study II with pravastatin in 11 healthy volunteers. In both studies, volunteers took 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested a single 40 mg dose of atorvastatin (study I) or pravastatin (study II) with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours later. In addition, subjects took 200 mL grapefruit juice or water three times a day on days 4 and 5 in study I. In study I, serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid, 2-hydroxyatorvastatin lactone, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 72 hours. In study II, pravastatin, pravastatin lactone, and active and total HMG-CoA reductase inhibitors were measured up to 24 hours.
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 (Cmax) was not significantly changed. The time of the peak concentration (tmax) and the elimination half-life (t1/2) of atorvastatin acid were increased (P < .01). The AUC(0-72) of atorvastatin lactone was increased 3.3-fold (P < .01) and the Cmax 2.6-fold (P < .01) by grapefruit juice, and the tmax and t1/2 were also increased (P < .05). Grapefruit juice decreased the Cmax (P < .001) and AUC(0-72) (P < .001) of 2-hydroxyatorvastatin acid and increased its tmax and t1/2 (P < .01). Grapefruit juice also decreased the Cmax (P < .001) and AUC(O-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 pravastatin was prolongation of the tmax of active HMG-CoA reductase inhibitors by grapefruit juice (P < .05).
Grapefruit juice significantly increased serum concentrations of atorvastatin acid, atorvastatin lactone, and active and total HMG-CoA reductase inhibitors, probably by decreasing CYP3A4-mediated first-pass metabolism of atorvastatin in the small intestine. On the other hand, grapefruit juice had no effect on the pharmacokinetics of pravastatin. Concomitant use of atorvastatin and at least large amounts of grapefruit juice should be avoided, or the dose of atorvastatin should be reduced accordingly.
葡萄柚汁可显著提高洛伐他汀和辛伐他汀的生物利用度。我们研究了葡萄柚汁对阿托伐他汀和普伐他汀药代动力学的影响。
进行了两项随机、两阶段交叉研究——研究I纳入12名健康志愿者服用阿托伐他汀，研究II纳入11名健康志愿者服用普伐他汀。在两项研究中，志愿者每天3次饮用200 mL双倍浓度葡萄柚汁或水，共2天。第3天，每位受试者单次服用40 mg阿托伐他汀（研究I）或普伐他汀（研究II），同时饮用200 mL葡萄柚汁或水，并在半小时和1个半小时后再饮用200 mL。此外，研究I的受试者在第4天和第5天每天3次饮用200 mL葡萄柚汁或水。在研究I中，测定了至72小时的阿托伐他汀酸、阿托伐他汀内酯、2-羟基阿托伐他汀酸、2-羟基阿托伐他汀内酯以及活性和总3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂的血清浓度。在研究II中，测定了至24小时的普伐他汀、普伐他汀内酯以及活性和总HMG-CoA还原酶抑制剂的血清浓度。
葡萄柚汁使阿托伐他汀酸从0至72小时的血清浓度-时间曲线下面积[AUC(0 - 72)]增加了2.5倍（P < .01），而血清峰浓度（Cmax）无显著变化。阿托伐他汀酸的峰浓度时间（tmax）和消除半衰期（t1/2）延长（P < .01）。葡萄柚汁使阿托伐他汀内酯的AUC(0 - 72)增加3.3倍（P < .01），Cmax增加2.6倍（P < .01），tmax和t1/2也延长（P < .05）。葡萄柚汁降低了（P < .001）2-羟基阿托伐他汀酸的Cmax和AUC(0 - 72)（P < .001），并延长了其tmax和t1/2（P < .01）。葡萄柚汁还降低了（P < .001）2-羟基阿托伐他汀内酯的Cmax和AUC(0 - 72)（P < .05）。葡萄柚汁使活性和总HMG-CoA还原酶抑制剂的AUC(0 - 72)值分别增加1.3倍（P < .05）和1.5倍（P < .01）。在研究II中，葡萄柚汁对普伐他汀药代动力学观察到的唯一显著变化是活性HMG-CoA还原酶抑制剂的tmax延长（P < .05）。
葡萄柚汁显著提高了阿托伐他汀酸、阿托伐他汀内酯以及活性和总HMG-CoA还原酶抑制剂的血清浓度，可能是通过减少小肠中CYP3A4介导的阿托伐他汀首过代谢。另一方面，葡萄柚汁对普伐他汀的药代动力学无影响。应避免阿托伐他汀与至少大量葡萄柚汁同时使用，或相应降低阿托伐他汀的剂量。
