RT Journal Article
SR Electronic
T1 Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 514
OP 522
DO 10.1124/dmd.108.024968
VO 37
IS 3
A1 Ngoc Ngo
A1 Zhixia Yan
A1 Tyler N. Graf
A1 Daniel R. Carrizosa
A1 Angela D. M. Kashuba
A1 E. Claire Dees
A1 Nicholas H. Oberlies
A1 Mary F. Paine
YR 2009
UL http://dmd.aspetjournals.org/content/37/3/514.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics