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Rapid CommunicationAccelerated Communication

Mechanisms of Enhanced Oral Availability of CYP3A4 Substrates by Grapefruit Constituents

Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins

Phyllissa Schmiedlin-Ren, David J. Edwards, Michael E. Fitzsimmons, Kan He, Kenneth S. Lown, Patrick M. Woster, Atiqur Rahman, Kenneth E. Thummel, Jeannine M. Fisher, Paul F. Hollenberg and Paul B. Watkins
Drug Metabolism and Disposition November 1997, 25 (11) 1228-1233;
Phyllissa Schmiedlin-Ren
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David J. Edwards
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Michael E. Fitzsimmons
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Kan He
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Kenneth S. Lown
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Patrick M. Woster
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Atiqur Rahman
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Kenneth E. Thummel
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Jeannine M. Fisher
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Paul F. Hollenberg
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Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins

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 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.

Footnotes

  • Send reprint requests to: Paul B. Watkins, M.D., University of Michigan Medical Center, Room A7119 University Hospital, Box 0108, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0108.

  • This work was supported by the NIGMS (GM 38149, P.B.W.), the NCRR (MO1 RR00042, University of Michigan General Clinical Research Center), and the NIEHS (1-P30-ES06639, D.J.E.).

  • ↵2 P. F. Hollenberg and K. He, data not shown, 1997.

  • ↵3 P. B. Watkins and M. E. Fitzsimmons, unpublished observations, 1997.

  • Abbreviations used are::
    DHB
    6′,7′-dihydroxybergamottin
    FC726
    furanocoumarin of M.W. 726
    • Received July 3, 1997.
    • Accepted August 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 11
1 Nov 1997
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Rapid CommunicationAccelerated Communication

Mechanisms of Enhanced Oral Availability of CYP3A4 Substrates by Grapefruit Constituents

Phyllissa Schmiedlin-Ren, David J. Edwards, Michael E. Fitzsimmons, Kan He, Kenneth S. Lown, Patrick M. Woster, Atiqur Rahman, Kenneth E. Thummel, Jeannine M. Fisher, Paul F. Hollenberg and Paul B. Watkins
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1228-1233;

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Rapid CommunicationAccelerated Communication

Mechanisms of Enhanced Oral Availability of CYP3A4 Substrates by Grapefruit Constituents

Phyllissa Schmiedlin-Ren, David J. Edwards, Michael E. Fitzsimmons, Kan He, Kenneth S. Lown, Patrick M. Woster, Atiqur Rahman, Kenneth E. Thummel, Jeannine M. Fisher, Paul F. Hollenberg and Paul B. Watkins
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1228-1233;
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