title: Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine.
abstract: 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.
  
  
  METHODS
  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 > or = 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 < or = 0.007), but not with furanocoumarin-free GFJ (P > or = 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 > or = 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.
authors.affiliation: School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA. mpaine@unc.edu
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
authors.forename: Wilbur W
authors.initials: WW
authors.lastname: Widmer
authors.forename: Susan N
authors.initials: SN
authors.lastname: Pusek
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Beavers
authors.forename: Anne B
authors.initials: AB
authors.lastname: Criss
authors.forename: Jennifer
authors.initials: J
authors.lastname: Snyder
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D019540:Area Under Curve; D001628:Beverages / Q000032:analysis; D018938:Caco-2 Cells; D002957:Citrus / Q000737:chemistry; D032083:Citrus paradisi / Q000737:chemistry*; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D018565:Food-Drug Interactions; D005638:Fruit / Q000737:chemistry; D011564:Furocoumarins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human