Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents: Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins

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  • Schmiedlin-Ren, Phyllissa
    • Other Affiliation: Department of Internal Medicine, University of Michigan Medical Center
  • Edwards, David J.
    • Other Affiliation: Department of Pharmacy Practice, College of Pharmacy and Allied Health Professions, Wayne State University
  • Fitzsimmons, Michael E.
    • Other Affiliation: Department of Internal Medicine, University of Michigan Medical Center; Division of Clinical Pharmacology, Center for Drug Evaluation and Research, United States Food and Drug Administration
  • He, Kan
    • Other Affiliation: Department of Pharmacology, University of Michigan Medical School
  • Lown, Kenneth S.
    • Other Affiliation: Department of Internal Medicine, University of Michigan Medical Center
  • Woster, Patrick M.
    • Other Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University
  • Rahman, Atiqur
    • Other Affiliation: Division of Clinical Pharmacology, Center for Drug Evaluation and Research, United States Food and Drug Administration
  • Thummel, Kenneth E.
    • Other Affiliation: Department of Pharmaceutics, University of Washington
  • Fisher, Jeannine M.
    • Other Affiliation: Department of Pharmaceutics, University of Washington
  • Hollenberg, Paul F.
    • Other Affiliation: Department of Pharmacology, University of Michigan Medical School
  • Watkins, Paul B.
    • Other Affiliation: Department of Internal Medicine, University of Michigan Medical Center
Abstract
  • 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 mM) 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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DOI
Identifier
  • 2-s2.0-0030696487
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Drug Metabolism and Disposition
Journal volume
  • 25
Journal issue
  • 11
Page start
  • 1228
Page end
  • 1233
Language
  • English
Version
  • Postprint
ISSN
  • 1521-009X

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