Seville Orange Interactions

Seville orange contains furanocoumarins that inhibit intestinal CYP3A4, the enzyme that clears the monacolin K in red yeast rice. Because monacolin K is chemically identical to the statin lovastatin and depends on CYP3A4 for its first-pass breakdown, blocking that enzyme raises systemic exposure to the active statin, increasing the risk of muscle-related side effects such as myopathy and, rarely, rhabdomyolysis.

Seville (bitter) orange contains the same furanocoumarins as grapefruit, including bergamottin and 6',7'-dihydroxybergamottin, which inactivate intestinal CYP3A4. A randomized crossover study showed Seville orange juice raised levels of the CYP3A4 drug felodipine to a degree comparable with grapefruit juice, while ordinary sweet orange juice had no effect. Because atorvastatin is metabolised by the same CYP3A4 pathway, Seville orange can raise atorvastatin levels and increase the risk of statin-related muscle injury.

Seville orange (bitter orange, Citrus aurantium) contains furanocoumarins that inhibit intestinal CYP3A4, the enzyme that breaks down cyclosporine in the gut wall. Unlike grapefruit, however, a controlled human study found that Seville orange juice did not meaningfully raise cyclosporine blood levels, because cyclosporine absorption also depends on intestinal P-glycoprotein, which Seville orange spares. Most transplant teams still advise avoiding bitter orange products as a precaution given variable furanocoumarin content and the high stakes of altered immunosuppressant levels.