Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine.

Background: We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates.

Objective: The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine.

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

Background: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear.

Objective: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine.

Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition.

Grapefruit juice elevates blood levels of some drugs taken orally, primarily by inhibiting intestinal CYP3A4-mediated first-pass metabolism. Two prominent furanocoumarins in the juice, 6',7'-dihydroxybergamottin (DHB) and bergamottin (BG), have been demonstrated as important contributors to grapefruit juice-drug interactions. Using CYP3A4-expressing Caco-2 cells and representative probes from distinct CYP3A4 substrate subgroups (midazolam, testosterone), we compared the time-dependent inhibitory properties of DHB and BG.

Two major grapefruit juice components differ in intestinal CYP3A4 inhibition kinetic and binding properties.

Bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB) are the most abundant furanocoumarins present in grapefruit juice and have been proposed as major intestinal CYP3A4 inhibitors contributing to grapefruit juice-drug interactions. The relative contribution of BG versus DHB to the interaction potential is unclear, in part due to inconsistencies in the literature regarding inhibitory potency. To resolve these inconsistencies, the inhibitory kinetics of each furanocoumarin toward CYP3A4 catalytic activity were systematically characterized using representative probes from two distinct CYP3A4 substrate subgroups (testosterone and midazolam).