Which medications interact with grapefruit?

Medications That Interact with Grapefruit

Patients taking medications metabolized by CYP3A4 or transported by P-glycoprotein/OATP proteins must completely avoid all grapefruit products due to the risk of increased drug bioavailability and potential toxicity. 1

Mechanism of Interaction

Grapefruit juice irreversibly inactivates intestinal CYP3A4 enzymes, reducing first-pass metabolism and increasing oral drug bioavailability, with effects persisting up to 24 hours after a single serving. 2 The interaction cannot be avoided by separating administration times because the mechanism involves enzyme destruction, not concurrent ingestion. 3, 2 Additionally, grapefruit inhibits P-glycoprotein and OATP transporters, further affecting drug absorption and distribution. 1, 4

High-Risk Medication Classes Requiring Complete Grapefruit Avoidance

Statins (HMG-CoA Reductase Inhibitors)

• Simvastatin, lovastatin, and atorvastatin carry significant risk of rhabdomyolysis when combined with grapefruit. 1, 5, 4
• Atorvastatin AUC increases by 37% and Cmax by 16% with 240 mL grapefruit juice; greater increases (AUC ratio up to 2.5, Cmax up to 1.71) occur with excessive consumption (≥750 mL to 1.2 liters daily). 6
• Safe alternatives: Pravastatin, fluvastatin, or rosuvastatin do not interact with grapefruit. 4

Immunosuppressants

• Cyclosporine and tacrolimus have narrow therapeutic indices and require complete grapefruit avoidance to prevent toxicity. 1
• Grapefruit juice can inhibit CYP3A4 in both gut and liver, increasing cyclosporine blood levels unpredictably; the effect is variable between individuals and may be long-lasting. 3
• Itraconazole (used in immunocompromised patients) shows a 30% decrease in AUC with concurrent grapefruit juice. 3

Calcium Channel Blockers

• Felodipine, nifedipine, nicardipine, nisoldipine, nitrendipine, and verapamil can cause excessive vasodilation and hypotension. 1, 4
• Verapamil interaction may result in atrioventricular conduction disorders. 4
• Safe alternative: Amlodipine does not significantly interact with grapefruit. 4

Antiarrhythmic Agents

• Amiodarone, quinidine, disopyramide, and propafenone risk enhanced drug toxicity with grapefruit consumption. 1, 4
• These drugs have high first-pass metabolism, making them particularly susceptible to grapefruit-induced bioavailability increases. 7

Benzodiazepines

• Benzodiazepines metabolized by CYP3A4 can reach toxic levels with grapefruit, causing excessive sedation, respiratory depression, cognitive impairment, and increased fall risk. 2
• Elderly patients face compounded danger due to increased sensitivity to benzodiazepine effects and higher baseline fall risk. 2

Antiretroviral Agents

• Saquinavir/ritonavir increases atorvastatin AUC by 3.93-fold and Cmax by 4.31-fold. 6
• Tipranavir/ritonavir increases atorvastatin AUC by 9.36-fold and Cmax by 8.58-fold. 6
• Multiple protease inhibitors significantly interact with CYP3A4 substrates. 3

Other High-Risk Medications

• Erectile dysfunction drugs (sildenafil, tadalafil, vardenafil): Risk serious systemic vasodilation, especially when combined with nitrates. 4
• Ergotamine (for migraine): May cause gangrene or stroke. 4
• Nimodipine (for stroke): May cause systemic hypotension. 4
• Carvedilol (for heart failure): Enhanced drug toxicity risk. 4
• Repaglinide (antidiabetic): May cause hypoglycemia. 4

Complete Elimination Required

Patients must eliminate ALL grapefruit products, including juice, fresh fruit, preserves, extracts, and zest. 1 The interaction persists for several days and cannot be eliminated by separating administration times. 3, 1

Safe Citrus Alternatives

Other citrus fruits such as oranges and lemons are safe alternatives and do not cause CYP3A4 inhibition. 1 However, pomegranate, star fruit, and certain Asian citrus varieties can also inhibit CYP3A4 and should be avoided. 1

Monitoring for Toxicity

Watch for signs of increased medication effect, including: 1

• Excessive sedation or confusion
• Respiratory depression
• Nausea or vomiting
• Muscle pain or weakness (with statins)
• Hypotension or dizziness
• Cardiac conduction abnormalities

Special Populations at Highest Risk

The elderly are at particular risk because they are frequently prescribed multiple interacting medications and commonly consume grapefruit juice. 4 This population requires especially vigilant counseling about complete grapefruit avoidance. 2