Grapefruit Drug Interactions - Mechanism of The Interaction

Mechanism of The Interaction

The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction and not flavonoids as was previously reported. The list of active furanocoumarins found in grapefruit juice includes: bergamottin, bergapten, bergaptol and 6',7'-dihydroxybergamottin.

This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic success and toxicity. Grapefruit juice inhibits the enzyme only within the intestines, not in the liver or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.

Another mechanism of interaction is possibly through the P-glycoprotein (Pgp) that is localized in the apical brush border of the enterocytes. Pgp transports lipophilic molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore their inhibition (both or alone) can markedly increase the bioavailability of a drug.

The interaction caused by grapefruit compounds lasts for up to 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.

The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolised to naringenin. There are also other flavonoids in grapefruit juice, in lower concentrations. Orange juice does not contain naringin in as high a concentration, instead containing hesperetin. It is sometimes recommended as a substitute. Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.