| Disease | WHEN SIMVASTATIN WAS TAKEN WITH GRAPEFRUIT JUICE, THE MEAN PEAK SERUM CONCENTRATION (C-MAX) AND THE MEAN AREA UNDER THE SERUM CONCENTRATION-TIME CURVE[AUC] OF SIMVASTATIN WERE INCREASED 12.0-FOLD (P<0.001) AND 13.5-FOLD (P<0.001), RESPECTIVELY,
COMPARED WITH CONTROL. WHEN SIMVASTATIN WAS GIVEN 3 DAYS AFTER INGESTION OF GRAPEFRUIT JUICE, THE C-MAX AND AUC WERE INCREASED 1.5-FOLD (P=0.12) AND 1.4-FOLD (P=0.09), RESPECTIVELY, COMPARED WITH CONTROL. SEVEN DAYS AFTER INGESTION OF
GRAPEFRUIT JUICE, NO DIFFERENCES IN THE C-MAX OR AUC OF SIMVASTATIN WERE SEEN. THE MEAN C-MAX AND AUC OF SIMVASTATIN ACID WERE INCREASED 5.0-FOLD AND 4.5-FOLD, RESPECTIVELY (P<0.001), COMPARED WITH CONTROL WHEN SIMVASTATIN WAS TAKEN WITH
GRAPEFRUIT JUICE AND 1.7-FOLD (P<0.01) 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. |