title: A modified grapefruit juice eliminates two compound classes as major mediators of the grapefruit juice-fexofenadine interaction: an in vitro-in vivo "connect".
abstract: The grapefruit juice (GFJ)-fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)-mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified GFJ devoid of furanocoumarins (~99%) and polymethoxyflavones (~90%) on fexofenadine disposition were compared to effects of the original juice. Extracts of both juices inhibited estrone 3-sulfate and fexofenadine uptake by similar extents in OATP-transfected cells (~50% and ~25%, respectively). Healthy volunteers (n = 18) were administered fexofenadine (120 mg) with water, GFJ, or modified GFJ (240 mL) by randomized, three-way crossover design. Compared to water, both juices decreased fexofenadine geometric mean AUC and C(max) by ~25% (P ≤ .008 and P ≤ .011, respectively), with no effect on terminal half-life (P = .11). Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the GFJ-fexofenadine interaction.
authors.affiliation: Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Won
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vandermolen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Wilbur W
authors.initials: WW
authors.lastname: Widmer
authors.forename: Yolanda V
authors.initials: YV
authors.lastname: Scarlett
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
mesh_terms: D000328:Adult; D000818:Animals; D018926:Anti-Allergic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001628:Beverages / Q000032:analysis; D019556:COS Cells; D002522:Chlorocebus aethiops; D032083:Citrus paradisi; D003374:Coumarins / Q000032:analysis; D018592:Cross-Over Studies; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000032:analysis; D018565:Food-Drug Interactions; D005638:Fruit; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D018926:Anti-Allergic Agents; D003374:Coumarins; D005419:Flavonoids; D027361:Organic Anion Transporters; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; D004970:Estrone; D016593:Terfenadine; C093230:fexofenadine; C017296:estrone sulfate
keywords: clinical pharmacology; clinical research; gastrointestinal; pharmacokinetics and drug metabolism