Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.