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Research ArticleArticle

Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans

Ngoc Ngo, Zhixia Yan, Tyler N. Graf, Daniel R. Carrizosa, Angela D. M. Kashuba, E. Claire Dees, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition March 2009, 37 (3) 514-522; DOI: https://doi.org/10.1124/dmd.108.024968
Ngoc Ngo
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Zhixia Yan
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Tyler N. Graf
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Daniel R. Carrizosa
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Angela D. M. Kashuba
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E. Claire Dees
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Nicholas H. Oberlies
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Mary F. Paine
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Abstract

An in vivo study in rats showed a cranberry juice product to inhibit the intestinal first-pass metabolism of the CYP3A substrate nifedipine. However, a clinical study involving the CYP3A probe substrate midazolam and a different cranberry juice product showed no interaction. Because the composition of bioactive components in natural products can vary substantially, a systematic in vitro-in vivo approach was taken to identify a cranberry juice capable of inhibiting enteric CYP3A in humans. First, the effects of five cranberry juices, coded A through E, were evaluated on midazolam 1′-hydroxylation activity in human intestinal microsomes. Juice E was the most potent, ablating activity at 0.5% juice (v/v) relative to control. Second, juice E was fractionated to generate hexane-, chloroform-, butanol-, and aqueous-soluble fractions. The hexane- and chloroform-soluble fractions at 50 μg/ml were the most potent, inhibiting by 77 and 63%, respectively, suggesting that the CYP3A inhibitors reside largely in these more lipophilic fractions. Finally, juice E was evaluated on the oral pharmacokinetics of midazolam in 16 healthy volunteers. Relative to water, juice E significantly increased the geometric mean area under the curve (AUC)0-∞ of midazolam by ∼30% (p = 0.001), decreased the geometric mean 1′-hydroxymidazolam/midazolam AUC0-∞ ratio by ∼40% (p < 0.001), and had no effect on geometric mean terminal half-life, indicating inhibition of enteric, but not hepatic, CYP3A-mediated first-pass metabolism of midazolam. This approach both showed a potential drug interaction liability with cranberry juice and substantiated that rigorous in vitro characterization of dietary substances is required before initiation of clinical drug-diet interaction studies.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM077482]; the National Institutes of Health National Center for Research Resources [Grant M01-RR000046]; the University of North Carolina Research Council; and the University of Washington School of Pharmacy Elmer M. Plein Endowed Research Fund.

  • Parts of this work were previously presented as follows: Ngo M, Dees EC, and Paine MF (2007) Cranberry juice delays midazolam absorption in healthy volunteers. American Society for Clinical Pharmacology and Therapeutics Meeting; 2007 Mar 21–24; Anaheim, CA; American Society for Clinical Pharmacology and Therapeutics, Alexandria, VA; Ngo N, Yan Z, Graf TN, Carrizosa DR, Dees EC, Oberlies NH, and Paine MF (2008) Identification of a cranberry juice product capable of inhibiting enteric CYP3A-mediated first-pass metabolism in humans. 7th Annual Oxford International Conference on the Science of Botanicals and the American Society of Pharmacognosy 4th Interim Meeting; 2008 Apr 12–16; Oxford, MS. National Center for Natural Products Research, Oxford, MS.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.024968.

  • ABBREVIATIONS: UTI, urinary tract infection; CYP3A, cytochrome P450 3A; AUC, area under the curve; P-gp, P-glycoprotein; HIM, human intestinal microsome; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; rCYP3A, recombinant CYP3A; TEER, transepithelial electrical resistance; Papp, apparent permeability coefficient; SPE, solid-phase extraction; ANOVA, analysis of variance.

  • ↵1 Current affiliation: Clinical Pharmacology, Quintiles Transnational, Overland Park, Kansas.

    • Received September 29, 2008.
    • Accepted December 23, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (3)
Drug Metabolism and Disposition
Vol. 37, Issue 3
1 Mar 2009
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Research ArticleArticle

Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans

Ngoc Ngo, Zhixia Yan, Tyler N. Graf, Daniel R. Carrizosa, Angela D. M. Kashuba, E. Claire Dees, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition March 1, 2009, 37 (3) 514-522; DOI: https://doi.org/10.1124/dmd.108.024968

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Research ArticleArticle

Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans

Ngoc Ngo, Zhixia Yan, Tyler N. Graf, Daniel R. Carrizosa, Angela D. M. Kashuba, E. Claire Dees, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition March 1, 2009, 37 (3) 514-522; DOI: https://doi.org/10.1124/dmd.108.024968
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