How does grapefruit cause drug interactions?

Grapefruit is an irreversible inhibitor of the major drug-metabolizing enzyme CYP3A4. CYP3A4 is a cytochrome P450 enzyme found predominantly in the liver and intestines. It is involved in the breakdown and elimination of around half of all available medications. Medications metabolized by CYP3A4 are called CYP3A4 substrates.^[1]

Grapefruit contains certain compounds — furanocoumarins — that can form strong and stable covalent bonds with CYP3A4, primarily in the intestine. This renders the enzyme inactive and impairs the body’s ability to metabolize the medication.^[1] Most of the time, this leads to higher-than-intended levels of the drug in the body, which can cause side effects and even toxicity. Additionally, some medications called prodrugs rely on CYP3A4 to convert them into an active form. In these cases, the medications may be less effective, which could result in treatment failure.

Because the inhibition of CYP3A4 by grapefruit is irreversible, CYP3A4 enzyme activity remains suboptimal until the body makes new enzymes or until the epithelial lining of the intestine is shed, which usually takes upwards of 24 hours.^[2]

To complicate matters further, grapefruit also seems to inhibit the drug efflux pump p-glycoprotein (P-gp) and the organic anion-transporting polypeptide (OATP) transporters OATP1A2 and OATP2B1. However, these effects are not consistently found and likely contribute only minorly to grapefruit’s drug interactions.^[1][3][4]