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Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine^1,2,3

¹ From the School of Pharmacy (MFP), the General Clinical Research Center (SNP, ABC, and PBW), and the Department of Medicine (KLB, JS, and PBW), University of North Carolina, Chapel Hill, NC; and the US Department of Agriculture, Citrus and Subtropical Products Laboratory, Winter Haven, FL (WWW)

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 [³H]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^–1, 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 [³H]cyclosporine 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.