Identification of a cranberry juice product that inhibits enteric CYP3A-mediated first-pass metabolism in humans.
Drug Metab Dispos
; 37(3): 514-22, 2009 Mar.
Article
em En
| MEDLINE
| ID: mdl-19114462
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Bebidas
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Vaccinium macrocarpon
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Citocromo P-450 CYP3A
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Intestinos
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Drug Metab Dispos
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos