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Vol. 25, Issue 11, 1228-1233, 1997
Department of Internal Medicine, University of Michigan Medical Center (P.S.-R., M.E.F., K.S.L., P.B.W.); Department of Pharmacy Practice (D.J.E.) and Pharmaceutical Sciences (P.M.W.), College of Pharmacy and Allied Health Professions, Wayne State University; Department of Pharmacology, University of Michigan Medical School (P.F.H., K.H.); Division of Clinical Pharmacology, Center for Drug Evaluation and Research, United States Food and Drug Administration (A.R., M.E.F.); Department of Pharmaceutics, University of Washington (K.E.T., J.M.F.)
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.
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