RT Journal Article
SR Electronic
T1 Mechanisms of Enhanced Oral Availability of CYP3A4 Substrates by Grapefruit Constituents
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1228
OP 1233
VO 25
IS 11
A1 Schmiedlin-Ren, Phyllissa
A1 Edwards, David J.
A1 Fitzsimmons, Michael E.
A1 He, Kan
A1 Lown, Kenneth S.
A1 Woster, Patrick M.
A1 Rahman, Atiqur
A1 Thummel, Kenneth E.
A1 Fisher, Jeannine M.
A1 Hollenberg, Paul F.
A1 Watkins, Paul B.
YR 1997
UL http://dmd.aspetjournals.org/content/25/11/1228.abstract
AB Grapefruit juice increases the oral availability of a variety of CYP3A4 substrates. It has been shown that recurrent grapefruit juice ingestion results in a loss of CYP3A4 from the small bowel epithelium. We now show that the reduction in intestinal CYP3A4 concentration is rapid; a 47% decrease occurred in a healthy volunteer within 4 hr after consuming grapefruit juice. To identify the specific components of the juice responsible for this effect, we used a recently developed Caco-2 cell culture model of human intestinal epithelium that expresses catalytically active CYP3A4. We found that grapefruit oil and two furanocoumarin constituents (6′,7′-dihydroxybergamottin and a closely related dimer) caused a dose-dependent fall in CYP3A4 catalytic activity and immunoreactive CYP3A4 concentration. The effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall, consistent with previous results obtained in vivo. Assays of various juices confirmed that 6′,7′-dihydroxybergamottin is the major furanocoumarin present and, although its concentration varies significantly among types and brands of grapefruit juice, it is consistently present in concentrations exceeding the IC50 (1 μM) for loss of midazolam 1′-hydroxylase activity determined in the Caco-2 cells. Studies with recombinant CYP3A4 revealed that 6′,7′-dihydroxybergamottin is a mechanism-based inactivator, which supports the idea that loss of CYP3A4 results from accelerated degradation of the enzyme. We conclude that the effect of grapefruit juice on oral availability of CYP3A4 substrates can be largely accounted for by the presence of 6′,7′-dihydroxybergamottin although other furanocoumarins probably also contribute. The American Society for Pharmacology and Experimental Therapeutics