Simvastatin Interactions

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

Red yeast rice contains monacolin K, which is chemically identical to the prescription statin lovastatin. Adding it to simvastatin stacks two statins with similar mechanisms and metabolism, sharply increasing the risk of myopathy, rhabdomyolysis, and liver injury.

St. John's wort induces intestinal and hepatic CYP3A4 and P-glycoprotein, sharply increasing simvastatin's first-pass metabolism. In a crossover study of healthy adults, the AUC of active simvastatin hydroxy acid was cut roughly in half (to about 48% of placebo).

Pomelo (Citrus maxima) contains furanocoumarins that irreversibly inhibit intestinal CYP3A4, the enzyme that metabolizes simvastatin during first-pass absorption. With CYP3A4 disabled, simvastatin plasma concentrations rise substantially, increasing the risk of myopathy and rhabdomyolysis.

Simvastatin inhibits HMG-CoA reductase, the enzyme upstream of both cholesterol and coenzyme Q10 synthesis. This produces a measurable decline in circulating CoQ10 and may contribute to mitochondrial dysfunction underlying statin-associated muscle symptoms.

Simvastatin is extensively metabolized by CYP3A4, and berberine inhibits CYP3A4 in vitro, which can raise simvastatin levels and increase the risk of myopathy and rhabdomyolysis. The interaction is bidirectional in some models (induction is also possible), making net effect unpredictable.

Simvastatin is heavily dependent on CYP3A4 for first-pass and systemic clearance, and CBD inhibits CYP3A4. Co-administration is expected to raise simvastatin and active-metabolite exposure, increasing the risk of muscle pain, transaminase elevation, and rare rhabdomyolysis.

Blood orange (Citrus sinensis var.) is a sweet orange and does not contain the furanocoumarins (bergamottin, 6',7'-dihydroxybergamottin) that drive the grapefruit-statin interaction. Published reviews of citrus furanocoumarin content list blood orange among the sweet oranges as essentially free of clinically significant CYP3A4-inhibiting compounds.