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. 2000 Oct;68(4):384-90. doi: 10.1067/mcp.2000.110216.
Grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism. We wanted to investigate how long the inhibitory effect of grapefruit juice lasts, with the CYP3A4 substrate simvastatin used as a model drug.
This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40 mg simvastatin with water (control), with "high-dose" grapefruit juice (200 mL double-strength grapefruit juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of "high-dose" grapefruit juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry up to 12 hours.
When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-infinity)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-infinity) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-infinity) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of grapefruit juice, no differences in the Cmax or AUC(0-infinity) of simvastatin were seen. The mean Cmax and AUC(0-infinity) of simvastatin acid were increased 5.0-fold and 4.5-fold, respectively (P < .001), compared with control when simvastatin was taken with grapefruit juice and 1.7-fold (P < .01) when it was taken 24 hours after ingestion of grapefruit juice. After an interval of 3 or 7 days between ingestion of grapefruit juice and simvastatin, the pharmacokinetic variables of simvastatin acid did not differ significantly from those in the control phase.
When simvastatin is taken 24 hours after ingestion of "high-dose" grapefruit juice, the effect of grapefruit juice on the AUC of simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and simvastatin. The interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice.
葡萄柚汁是CYP3A4介导的药物代谢的强效抑制剂。我们想用辛伐他汀作为模型药物来研究葡萄柚汁的抑制作用能持续多久。
这项交叉研究包括5个研究日，在此期间，10名健康志愿者用水服用40毫克辛伐他汀（对照），用“高剂量”葡萄柚汁（双倍浓度葡萄柚汁200毫升，每天3次，共3天），或在摄入“高剂量”葡萄柚汁后1、3和7天服用。出于安全考虑，该研究分三个部分进行，以便在研究日之间有不含辛伐他汀的日子。通过液相色谱 - 串联质谱法测量辛伐他汀和辛伐他汀酸的血清浓度，最长测量12小时。
当辛伐他汀与葡萄柚汁一起服用时，与对照相比，辛伐他汀的平均血清峰浓度（Cmax）和血清浓度 - 时间曲线下的平均面积[AUC(0 - ∞)]分别增加了12.0倍（P <.001）和13.5倍（P <.001）。在摄入最后一剂葡萄柚汁24小时后服用辛伐他汀时，与对照相比，Cmax和AUC(0 - ∞)分别增加了2.4倍（P <.01）和2.1倍（P <.001）。在摄入葡萄柚汁3天后服用辛伐他汀时，与对照相比，Cmax和AUC(0 - ∞)分别增加了1.5倍（P =.12）和1.4倍（P =.09）。在摄入葡萄柚汁7天后，未观察到辛伐他汀的Cmax或AUC(0 - ∞)有差异。与对照相比，当辛伐他汀与葡萄柚汁一起服用时，辛伐他汀酸的平均Cmax和AUC(0 - ∞)分别增加了5.0倍和4.5倍（P <.001），在摄入葡萄柚汁24小时后服用时增加了1.7倍（P <.01）。在摄入葡萄柚汁和辛伐他汀之间间隔3或7天后，辛伐他汀酸的药代动力学变量与对照阶段相比无显著差异。
在摄入“高剂量”葡萄柚汁24小时后服用辛伐他汀时，葡萄柚汁对辛伐他汀AUC的影响仅约为同时摄入葡萄柚汁和辛伐他汀时观察到的影响的10%。即使是大量葡萄柚汁与CYP3A4底物的相互作用潜力在摄入最后一剂葡萄柚汁后的3至7天内消失。
