title: Identification of a cranberry juice product that inhibits enteric CYP3A-mediated first-pass metabolism in humans.
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 microg/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-infinity) of midazolam by approximately 30% (p=0.001), decreased the geometric mean 1'-hydroxymidazolam/midazolam AUC(0-infinity) ratio by approximately 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.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Ngo
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Yan
authors.forename: Tyler N
authors.initials: TN
authors.lastname: Graf
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrizosa
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D029799:Vaccinium macrocarpon
chemical_list: D051544:Cytochrome P-450 CYP3A; D008874:Midazolam