Identification of a cranberry juice product that inhibits enteric CYP3A-mediated first-pass metabolism in humans.
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.
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Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
Yan
Zhixia
Z
Graf
Tyler N
TN
Carrizosa
Daniel R
DR
Kashuba
Angela D M
AD
Dees
E Claire
EC
Oberlies
Nicholas H
NH
Paine
Mary F
MF
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
D051544:Cytochrome P-450 CYP3A; D008874:Midazolam