Grapefruit Interactions

Grapefruit inhibits CYP3A4 enzyme, dramatically increasing statin blood levels and risk of muscle damage (rhabdomyolysis).

Sirolimus is a CYP3A4 and P-glycoprotein substrate with a narrow therapeutic window and high baseline interpatient variability. The FDA-approved Rapamune label states that grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus and must not be taken with or used to dilute the drug, because unpredictable, large rises in blood levels can cause nephrotoxicity, infection, and graft injury.

Grapefruit juice blocks intestinal CYP3A4, dramatically increasing lovastatin and lovastatin acid exposure. A controlled study showed lovastatin Cmax rose ~12-fold and AUC ~15-fold after high-dose grapefruit juice, sharply raising the risk of myopathy and rhabdomyolysis.

Grapefruit can increase atorvastatin levels, raising risk of side effects.

Grapefruit furanocoumarins irreversibly inhibit intestinal CYP3A4, increasing tacrolimus AUC by roughly 28% and Cmax by up to 73%. Case reports describe trough levels tripling after grapefruit ingestion, producing nephrotoxicity and neurotoxicity.

Grapefruit juice irreversibly inhibits intestinal CYP3A4, reducing first-pass metabolism of carbamazepine and increasing its bioavailability. Clinical study in epilepsy patients showed AUC rose by roughly 40 percent with concomitant grapefruit juice, pushing plasma levels toward the toxic range.

Methadone is partially metabolized by CYP3A4 (and CYP2B6). Grapefruit juice inhibits intestinal CYP3A4 and can raise methadone plasma concentrations, with case reports of opioid toxicity after sustained grapefruit juice intake. Higher methadone levels also increase the risk of QT prolongation and torsades de pointes.

Oxycodone undergoes CYP3A4-mediated metabolism to noroxycodone. A controlled crossover study in healthy volunteers showed grapefruit juice increased oxycodone AUC 1.7-fold, peak concentration 1.5-fold, and half-life 1.2-fold, while reducing formation of inactive noroxycodone, raising the risk of sedation and respiratory depression.

Grapefruit juice inhibits intestinal CYP3A4, raising oral amiodarone AUC by approximately 50% and peak levels by 84% while abolishing production of its active metabolite N-desethylamiodarone. The FDA-approved Pacerone label explicitly states grapefruit juice should not be consumed during oral amiodarone treatment.

Lurasidone is primarily metabolized by CYP3A4 and is highly sensitive to CYP3A4 inhibitors. The FDA-approved Latuda prescribing information specifically states that grapefruit and grapefruit juice should be avoided in patients taking lurasidone because they inhibit CYP3A4 and can substantially raise lurasidone concentrations.

Quetiapine is metabolized primarily by CYP3A4. Grapefruit juice inhibits intestinal CYP3A4 and can substantially increase quetiapine plasma concentrations; a documented case report describes quetiapine toxicity in a young woman who consumed a gallon of grapefruit juice over 24 hours while on a stable dose.

Grapefruit juice contains furanocoumarins that irreversibly inhibit intestinal CYP3A4, raising cyclosporine bioavailability by 35-60% and increasing the risk of nephrotoxicity, hypertension, and neurotoxicity. The effect can persist for 24 hours or longer after a single glass.

Buspirone undergoes extensive first-pass metabolism by intestinal and hepatic CYP3A4. A controlled study showed grapefruit juice increased buspirone AUC 9.2-fold and peak plasma concentration 4.3-fold, dramatically amplifying sedation, dizziness, and serotonergic effects.

Grapefruit may reduce the conversion of losartan to its active form, decreasing effectiveness.

Grapefruit juice has been shown in healthy-volunteer studies to reduce itraconazole capsule peak concentrations by roughly 35 percent and overall AUC by about 43 percent, likely through changes in gastric pH and intestinal effects that impair the capsule's absorption.

Fluconazole is a moderate inhibitor of CYP3A4 and grapefruit juice inhibits intestinal CYP3A4; the inhibition is additive, which can raise plasma levels of any third drug that depends on CYP3A4 for clearance.

Sildenafil is metabolized primarily by CYP3A4. Grapefruit juice inhibits intestinal CYP3A4 and modestly increases sildenafil AUC by about 23 percent while delaying peak concentration, which can worsen the headache, flushing, dizziness, and hypotension typical of PDE5 inhibitors.

Grapefruit juice inhibits intestinal CYP3A4 and increases diltiazem exposure (AUC) by roughly 20% in healthy volunteers, with high inter-individual variability. The increase can amplify the drug's negative chronotropic and hypotensive effects.

Grapefruit may slightly increase CoQ10 absorption.

Unlike simvastatin, lovastatin, and atorvastatin, pravastatin is not significantly metabolized by CYP3A4, so grapefruit juice does not meaningfully change its plasma exposure. Clinical pharmacokinetic studies show no significant effect of grapefruit juice on pravastatin disposition.

Amlodipine is a CYP3A4 substrate, but unlike other dihydropyridines (felodipine, nisoldipine), its high oral bioavailability and slow elimination mean grapefruit juice does not meaningfully alter its pharmacokinetics in controlled trials. Some product labels and consumer references still list a theoretical interaction.

Grapefruit juice contains furanocoumarins that inhibit intestinal CYP3A4, the enzyme that partially metabolizes alprazolam. The interaction can raise alprazolam blood levels and prolong sedation, although the magnitude is modest compared to other benzodiazepines because alprazolam has high oral bioavailability.