title: The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans.
abstract: OBJECTIVE
  The objective was to determine the effects of the SLCO2B1 c.1457C> T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans.
  
  
  METHODS
  Individuals were divided based on the genotype of SLCO2B1 c.1457C> T (n = 14, c.[1457C]+ c.[= ] 5,c.[1457C]+ c.[1457C> T] 5, and c.[1457C> T]+c.[1457C> T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system.
  
  
  RESULTS
  When fexofenadine was administered with water, subjects with c.[1457C> T] allele showed a significant decrease in fexofenadine in the area under the plasma concentration-time curve (AUC) compared with c.[1457C] + c[= ] subjects (1110 ± 347 vs. 1762 ± 542 ng . h/ml, P< 0.05). When administered with apple juice, a significant decrease in the fexofenadine AUC was observed compared with water (1342 ± 519 vs. 284 ± 79.2 ng . h/ml, P < 0.05). The apple juice induced decrease in fexofenadine AUC was significantly lower in subjects carrying the c.[1457C> T] allele. Neither the genotype nor the apple juice showed significant effects on the pharmacokinetics of midazolam except for a marginally significant decrease in Cmax after administration with apple juice. The uptake of fexofenadine by OATP2B1 cRNA-injected oocytes was significantly higher than that by water-injected oocytes. Apple juice, but not midazolam, significantly decreased the uptake of fexofenadine by OATP2B1 cRNA-injected oocytes.
  
  
  CONCLUSIONS
  The results suggest that fexofenadine is a substrate of OATP2B1, and the transport function of OATP2B1 is subject to the genotype of SLCO2B1 c.1457C> T and apple juice. It is likely that apple juice has little effect on CYP3A.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Imanaga
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kotegawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Imai
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Yoshizato
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Ohyama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D000328:Adult; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001628:Beverages; D001692:Biological Transport; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D027845:Malus; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D018926:Anti-Allergic Agents; D018757:GABA Modulators; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D016593:Terfenadine; C093230:fexofenadine; D008874:Midazolam