GRAPEFRUIT JUICE-SIMVASTATIN INTERACTION - EFFECT ON SERUM CONCENTRATIONS OF SIMVASTATIN, SIMVASTATIN ACID, AND HMG-COA REDUCTASE INHIBITORS

Background: Simvastatin is a cholesterol-lowering agent that is metabo lized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered simvastatin. Methods: In a ra ndomized, 2-phase crossover study, 10 healthy volunteers took either 2 00 mL double-strength grapefruit juice or water 3 times a day for 2 da ys. On day 3, each subject ingested 60 mg simvastatin with either 200 mt grapefruit juice or water, and an additional 200 mt was ingested 1/ 2 and 1 1/2 hours after simvastatin administration. Serum concentratio ns of simvastatin and simvastatin acid were measured by liquid chromat ography-tandem mass spectrometry (LC-MS-MS) and those of active (naive ) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. Resul ts: Grapefruit juice increased the mean peak serum concentration (C-ma x) of unchanged simvastatin about 9-fold (range, 5.1-fold to 31.4-fold ; P <.01) and the mean area under the serum simvastatin concentration- time curve [AUC(0-infinity)] 16-fold (range, 9.0-fold to 37.7-fold; P <.05). The mean C-max and AUC(0-infinity) of simvastatin acid were bot h increased about 7-fold (P <.01). Grapefruit juice increased the mean AUC(0-infinity) of active and total HMG-CoA reductase inhibitors 2.4- fold (P <.01) and 3.6-fold (P <.01), respectively. The time of the pea k concentration of active and total HMG-CoA reductase inhibitors was i ncreased by grapefruit juice (P <.05). Conclusion: Grapefruit juice gr eatly increased serum concentrations of simvastatin and simvastatin ac id and, to a lesser extent, those of active and total HMG-CoA reductas e inhibitors. The probable mechanism of this interaction was inhibitio n of CYP3A4-mediated first-pass metabolism of simvastatin by grapefrui t juice in the small intestine. Concomitant use of grapefruit juice an d simvastatin, at least in large amounts, should be avoided, or the do se of simvastatin should be greatly reduced.