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
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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.
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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.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.024968.
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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.
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↵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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