6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect

Area of Science:

• Pharmacology and Drug Metabolism

Background:

• Grapefruit juice is known to interact with various medications.
• Cytochrome P450 3A4 (CYP3A4) is a key enzyme in drug metabolism, primarily in the intestine.
• 6',7'-dihydroxybergamottin (DHB) is a furanocoumarin found in grapefruit juice.

Purpose of the Study:

• To determine the contribution of 6',7'-dihydroxybergamottin (DHB) to grapefruit juice's inhibitory effect on intestinal CYP3A4.
• To investigate the impact of DHB on the pharmacokinetics of felodipine, a CYP3A4 substrate.

Main Methods:

• An aqueous extract (serum) of grapefruit juice was prepared.
• Concentrations of furanocoumarins, including DHB, were measured in whole grapefruit juice and serum using HPLC and LC-MS/MS.
• Healthy volunteers ingested felodipine with whole grapefruit juice, orange juice-containing serum, or plain orange juice.
• In vitro studies assessed the inhibition of CYP3A4 activity and protein levels by serum and purified DHB.

Main Results:

• DHB concentration in grapefruit juice serum was comparable to whole grapefruit juice.
• Orange juice-containing serum significantly increased felodipine's plasma concentration (AUC by 1.9-fold, Cmax by 1.7-fold).
• Both grapefruit juice serum and purified DHB demonstrated significant reversible and mechanism-based inhibition of CYP3A4 activity in vitro, with similar effects on CYP3A4 protein loss in Caco-2 cells.

Conclusions:

• The interaction between grapefruit juice and felodipine is largely due to DHB.
• DHB is identified as a significant contributor to the overall grapefruit juice effect on drug metabolism.