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Research ArticleArticle

TWO MAJOR GRAPEFRUIT JUICE COMPONENTS DIFFER IN INTESTINAL CYP3A4 INHIBITION KINETIC AND BINDING PROPERTIES

Mary F. Paine, Anne B. Criss and Paul B. Watkins
Drug Metabolism and Disposition October 2004, 32 (10) 1146-1153; DOI: https://doi.org/10.1124/dmd.104.000547
Mary F. Paine
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Paul B. Watkins
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Abstract

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). With human intestinal microsomes, DHB was a substrate-independent reversible (Ki, ∼0.8 μM) and mechanism-based (KI, ∼3 μM; kinact, 0.3-0.4 min-1) inhibitor of CYP3A4. In contrast, BG was a substrate-dependent reversible inhibitor, with a Ki (13 μM) using midazolam that was 8-fold greater than that using testosterone, but a substrate-independent mechanism-based inhibitor (KI, ∼25 μM; kinact, ∼0.35 min-1). Similar trends resulted with cDNA-expressed CYP3A4, only the KI values for BG were ∼10-fold lower than with microsomes. This seemed to reflect a much greater degree of microsomal protein binding by BG compared with DHB. Differential inhibition kinetics and binding properties between BG and DHB could account in part for the apparent in vitro inconsistencies in the literature. Results also emphasize the importance of appropriate substrate selection when designing inhibition studies involving dietary constituents.

Footnotes

  • This work was supported by the National Institutes of Health Grants GM38149 and RR00046.

  • doi:10.1124/dmd.104.000547.

  • ABBREVIATIONS: BG, bergamottin; DHB, 6′,7′-dihydroxybergamottin; HIM, human intestinal microsomes; 6β-OH TST, 6β-hydroxytestosterone; 1′-OH MDZ, 1′-hydroxymidazolam; HPLC, high-performance liquid chromatography; P450, cytochrome P450.

    • Received May 7, 2004.
    • Accepted July 12, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (10)
Drug Metabolism and Disposition
Vol. 32, Issue 10
1 Oct 2004
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Research ArticleArticle

TWO MAJOR GRAPEFRUIT JUICE COMPONENTS DIFFER IN INTESTINAL CYP3A4 INHIBITION KINETIC AND BINDING PROPERTIES

Mary F. Paine, Anne B. Criss and Paul B. Watkins
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1146-1153; DOI: https://doi.org/10.1124/dmd.104.000547

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Research ArticleArticle

TWO MAJOR GRAPEFRUIT JUICE COMPONENTS DIFFER IN INTESTINAL CYP3A4 INHIBITION KINETIC AND BINDING PROPERTIES

Mary F. Paine, Anne B. Criss and Paul B. Watkins
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1146-1153; DOI: https://doi.org/10.1124/dmd.104.000547
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