Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine
| Autor: | Anne B. Criss, Mary F. Paine, Paul B. Watkins, Wilbur W. Widmer, Susan N. Pusek, Kimberly L. Beavers, Jennifer A. Snyder |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Citrus food.ingredient Medicine (miscellaneous) Pharmacology Grapefruit juice Beverages Furanocoumarin Food-Drug Interactions food Cytochrome P-450 Enzyme System In vivo Furocoumarins medicine Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors Orange juice Nutrition and Dietetics Chromatography Cross-Over Studies CYP3A4 Dose-Response Relationship Drug Chemistry Area under the curve Middle Aged Dose–response relationship Felodipine Area Under Curve Fruit Cyclosporine Cytochrome P-450 CYP3A Inhibitors Female Caco-2 Cells medicine.drug Citrus paradisi |
| Zdroj: | The American journal of clinical nutrition. 87(4) |
| ISSN: | 1938-3207 |
| Popis: | Background: We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. Objective: The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. Design: By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by ≥1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [ 3 H]cyclosporine translocation in Caco-2 cells were then compared. Results: The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P ≤ 0.007), but not with furanocoumarin-free GFJ (P ≥ 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) X 10 -3 h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL- respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7- 8 h, respectively; P ≥ 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [ 3 H]cydosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. Conclusions: Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein. |
| Databáze: | OpenAIRE |
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