Why grapefruit is on so many drug labels: CYP3A4 and furanocoumarins

Grapefruit is on the warning label of dozens of drugs because of a mechanism worth understanding rather than memorising. The mechanism Grapefruit contains furanocoumarins — chiefly bergamottin and 6',7'-dihydroxybergamottin. These are mechanism-based ("suicide") inhibitors of intestinal CYP3A4: they inactivate the enzyme in the gut wall, and the gut has to make new enzyme to recover. That is why the effect is slow to come and slow to go. What it does For a drug that is a CYP3A4 substrate and normally suffers heavy first-pass metabolism in the gut, knocking out intestinal CYP3A4 raises how much reaches the blood. The classic examples are some statins (simvastatin, lovastatin — not pravastatin or rosuvastatin, which are not CYP3A4 substrates), several calcium-channel blockers, and some immunosuppressants. The part people get wrong - It is the intestinal enzyme that matters most, so the interaction is largest for oral drugs with low baseline bioavailability. - Because it is mechanism-based, spacing the juice and the dose by a few hours does NOT avoid it; inhibition lasts until the gut regenerates enzyme, which is of the order of a day or more. - It is a dose-and-variety thing: whole fruit and double-strength juice matter more; the furanocoumarin content varies by product. Seville (bitter) oranges and pomelos carry furanocoumarins too; common sweet oranges essentially do not. Mechanism, isoforms and the induction/inhibition distinction are mapped here: https://wiki.soapbox.community/wiki/Cytochrome_P450_System_Inhibition_and_Induction Check this one against your own medicine's label — it is one of the best-documented food–drug interactions there is. Sources: FDA consumer update on grapefruit juice and medicine; Bailey DG et al., CMAJ 2013.