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ORIGINAL RESEARCH COMMUNICATION |
1 From the Division of Pharmacotherapy and Experimental Therapeutics (MFP and PBW), the General Clinical Research Center (MFP, HLH, SNP, ABC, and PBW), and the Department of Medicine (KLB and PBW), University of North Carolina, Chapel Hill, NC; the Citrus and Subtropical Products Laboratory, US Department of Agriculture, Winter Haven, FL (WWW); and the Research Triangle Institute, Research Triangle Park, NC (SSB and BFT).
Background: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear.
Objective: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine.
Design: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (
99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments.
Results: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58–270) nmol · h/L and 21 (7.6–50) nmol/L, respectively] than with that of orange juice [54 (29–150) nmol · h/L and 7.6 (3.4–13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23–120) nmol · h/L and 8.3 (3.0–16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5–6), 2.8 (1.5–4), and 2.5 (2–6) h, respectively] or terminal half-life [6.6 (4.2–13.6), 7.8 (4.4–13.2), and 6.8 (2.6–14.4) h, respectively].
Conclusion: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.
Key Words: Grapefruit juice • CYP3A4 • metabolism • drugs • interaction • intestine • first-pass metabolism • felodipine • furanocoumarins
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