Should patients avoid grapefruit juice consumption while taking 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.
Current medical advice is to avoid grapefruit juice consumption while taking a statin. The action of grapefruit juice on the effect of drugs was discovered by accident in 1989 in an experiment designed to examine the effect of ethanol on the action of felodipine, a calcium channel blocker. Grapefruit juice was used to mask the taste of alcohol but the results showed several-fold higher felodipine concentration in blood plasma than had been expected. Grapefruit juice has since been shown to interact with over 85 drugs, including statins, which are widely used to reduce low-density lipoprotein (LDL) cholesterol to help prevent cardiovascular disease.
The adverse effects of statins on muscles can range from mild discomfort (myalgia) to the more serious rhabdomyolysis, which requires hospitalization and, in extremely rare cases, causes death. Statins increase the risk of hyperglycemia, but the much greater cardiovascular benefits of statins outweigh this small increased risk, and statins are recommended in patients with diabetes. We here focus on rhabdomyolysis as the dominant adverse event of concern.
This review summarizes the pharmacokinetics of grapefruit juice–statin interactions, specifically, atorvastatin, simvastatin, and lovastatin, and quantifies how this interaction affects LDL cholesterol and ischemic heart disease risk and the risk of rhabdomyolysis, presenting results on which clinical advice can be based.
Chemistry of the Grapefruit Juice Effect
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Different statins vary in their bioavailability, half-life, and method of metabolic degradation (see Table 1). For example, as a consequence of their different half-lives, atorvastatin can be taken at any time during the day with a consistent efficacy, whereas simvastatin should be taken at night. Cytochrome P450 (CYP)3A4 is the major enzyme involved in the metabolic degradation of many statins, including atorvastatin, simvastatin, and lovastatin
The main agents responsible for the grapefruit juice effect on statins are bergamottin in fresh grapefruit and its derivative, 6′,7′-dihydroxybergamottin (DHB) in juice concentrate, which are furanocoumarins. Furanocoumarins are also found in other fruit (eg, pomegranates), and in vegetables (eg, parsnips and celery), however, they are especially concentrated in grapefruit juice and fresh grapefruits.
Kinetic studies reveal that both bergamottin and DHB inactivate CYP3A4. Studies have shown a 50% reduction in intestinal CYP3A4 concentration within 4 hours of drinking one serving of grapefruit juice (equivalent to the juice in one whole grapefruit).15, 17 Inhibiting the activity of CYP3A4 in the intestines presumably inhibits the presystemic degradation of statins and so increases their systemic bioavailability. Lovastatin, simvastatin, and atorvastatin are all metabolized by CYP3A4, while statins such as fluvastatin and rosuvastatin are metabolized by CYP2C9 (Table 1) and pravastatin is metabolized enzymatically in the liver. This explains why grapefruit juice interacts with atorvastatin, simvastatin, and lovastatin, but not with fluvastatin, rosuvastatin, or pravastatin. Removal of furanocoumarins from grapefruit juice eliminates the grapefruit juice effect.
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-Jonathan W. Lee, BS, Joan K. Morris, PhD, Nicholas J. Wald, FRS
This article originally appeared in the January 2016 issue of The American Journal of Medicine.
