Background: Grapefruit juice greatly increases the bioavailability of lovastatin and simvastatin. We studied the effect of grapefruit juice on the pharmacokinetics of atorvastatin and pravastatin.

Methods: 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.

Results: 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).

Conclusions: 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.

Aim: To determine whether customary exposure to grapefruit juice (GFJ) alters serum concentrations, effectiveness, and potential adverse effects of atorvastatin in patients requiring the medication.

Methods: Patients receiving extended treatment with atorvastatin (10, 20 or 40 mg day(-1)) at a stable dose received 300 ml day(-1) of 100% GFJ for a period of 90 days. One cohort of patients (arm A, n= 60) continued on their current dose of atorvastatin; the second cohort (arm B, n= 70) reduced the daily dose by 50%. Serum atorvastatin, lipid profile, liver functions, and creatine phosphokinase (CPK) were measured at baseline and at 30, 60, and 90 days after starting GFJ.

Results: In Arm A patients, co-ingestion of GFJ significantly elevated serum atorvastatin by 19% to 26% compared with baseline. Changes in lipid profile relative to baseline were negligible. There were no adverse effects on liver function tests or CPK. In arm B patients, serum atorvastatin declined by 12% to 25% compared to baseline, with a small but significant unfavourable effect in serum lipid profile. There were no adverse effects on liver function tests or CPK.

Conclusion: In patients on extended stable atorvastatin treatment, addition of daily GFJ in typical quantities slightly elevates serum atorvastatin concentrations, but has no meaningful effect on the serum lipid profile, and causes no detectable adverse liver or muscle effects. Reduction of atorvastatin dosage when moderate amounts of GFJ are co-ingested does not appear to be necessary.

We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3 widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80% (whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Grapefruit juice should not be contraindicated in people taking statins.

Over-the-counter supplements, medications, and foods: The Natural Medicines Comprehensive Database is the most frequently used resource to investigate over-the-counter supplements/medicines and their effects on statin medications. For ease, the most common interactions can be divided into major (do not use) and moderate (clinical outcome not severe). Concomitant ingestion of alcohol and statins, and other medications metabolized through the liver, can result in DDIs. Although no specific quantity recommendations are available, moderate amounts of alcohol (2 standard drinks in a 24-hour period) offer less concern for pharmacokinetic and pharmacodynamic effects than larger amounts. Grapefruit juice contains bergamottin, a natural furanocoumarin, which can inhibit CYP3A4 and OAT. This inhibitory effect can last for up to 24 hours. Either grapefruit juice should be avoided with statins or the quantity consumed should be kept to less than 60 mL. Separating administration of grapefruit juice and statins by 4 hours may limit the interaction.
Like grapefruit, sweet orange (citrus sinensis) juice may inhibit OATP. Tangerines are related to the sweet orange and may also have an interaction. Separation of the fruit or juice from statin administration by 4 hours may be advisable. St John's wort induces CYP3A4. There are noted major interactions between statins and St. John's wort, and this combination should be avoided. St. John's wort mediates P-gp. It will decrease metabolism of simvastatin and possibly atorvastatin, but not likely pravastatin, fluvastatin, or rosuvastatin. Red yeast rice is a popular nonprescription treatment for hyperlipidemia. Red yeast rice has varying amounts of monacolin K (similar to lovastatin). Products are not standardized and no red yeast rice product should be given to a patient taking a prescription statin.