Why do statins interact with grapefruit?

Statin-Grapefruit Juice Interaction: Mechanism and Clinical Implications

Grapefruit juice inhibits CYP3A4 enzymes and P-glycoprotein in the intestine, significantly increasing blood levels of certain statins and potentially raising the risk of myopathy and rhabdomyolysis. 1

Mechanism of Interaction

• Grapefruit juice is a potent inhibitor of the CYP3A4 enzyme system, which is responsible for the metabolism of several statins, particularly simvastatin, lovastatin, and to a lesser extent, atorvastatin 1
• Grapefruit juice also inhibits P-glycoprotein (P-gp), a transport protein that affects atorvastatin, lovastatin, pitavastatin, and simvastatin 1
• This inhibition prevents first-pass metabolism in the intestine, dramatically increasing bioavailability and serum concentrations of susceptible statins 2, 3

Impact on Specific Statins

Highly Affected Statins (CYP3A4 Substrates)

• Simvastatin: Grapefruit juice increases serum concentrations approximately 9-fold for peak levels and 16-fold for total exposure (AUC) 4
• Lovastatin: Grapefruit juice increases serum concentrations approximately 12-fold for peak levels and 15-fold for total exposure 2
• Atorvastatin: Moderately affected with approximately 2.5-fold increase in total exposure, though peak concentrations are less dramatically affected 5

Minimally or Unaffected Statins

• Pravastatin: No significant interaction with grapefruit juice as it is not metabolized by CYP3A4 5
• Fluvastatin: Primarily metabolized by CYP2C9, not significantly affected by grapefruit juice 1
• Rosuvastatin: Primarily metabolized by CYP2C9, minimal interaction with grapefruit juice 1
• Pitavastatin: Minimal CYP metabolism, less likely to interact significantly 1

Clinical Significance and Risk

• The FDA-approved product labeling for simvastatin explicitly states: "Avoid grapefruit juice when taking simvastatin" due to increased risk of myopathy and rhabdomyolysis 6
• Even one glass of grapefruit juice taken daily can considerably increase plasma concentrations of susceptible statins 3
• The timing of consumption matters - taking grapefruit juice at the same time as the statin produces a larger effect (260% increase for simvastatin/lovastatin) compared to taking it 12 hours apart (90% increase) 7

Management Recommendations

• For simvastatin and lovastatin: Completely avoid grapefruit juice consumption due to dramatic increases in drug levels 6, 2, 4
• For atorvastatin: Consider avoiding grapefruit juice or limiting consumption; if continued use is necessary, dose reduction may be required 5
• For pravastatin, fluvastatin, rosuvastatin, and pitavastatin: These statins can be used without specific restrictions regarding grapefruit juice 5
• When patients require statin therapy and regularly consume grapefruit juice, consider switching to pravastatin or fluvastatin which are not significantly affected by this interaction 1, 5

Monitoring for Patients at Risk

• Monitor for symptoms of myopathy (muscle pain, tenderness, or weakness) especially with fever or malaise in patients who may have consumed grapefruit juice while on susceptible statins 8
• Consider checking creatine kinase levels if symptoms develop in patients on statins who consume grapefruit juice 8

Remember that the magnitude of this interaction varies between individuals and depends on the amount of grapefruit juice consumed, timing of consumption relative to statin dosing, and individual differences in CYP3A4 activity 7, 3.