title: No major effects of vitamin D3 (1,25 dihydroxyvitamin D3) on absorption and pharmacokinetics of folic acid and fexofenadine in healthy volunteers.
abstract: OBJECTIVE
  In Caco-2 cells, folate uptake via the proton-coupled folate transporter (PCFT) increases significantly by a 3-day treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Additionally, mRNA content and protein expression of the transporter OATP1A2 were increased up to ninefold with 1,25(OH)2D3. We investigated whether these in vitro findings can be confirmed in humans in vivo.
  
  
  METHODS
  Ten healthy volunteers (six women) received 5 mg folic acid orally once before and once together with the last intake of a 10-day course of 0.5 μg 1,25(OH)2D3 orally. One hundred twenty milligrams fexofenadine, an OATP1A2 substrate, was taken in 1 day before the first folic acid intake, and again on the ninth day of 1,25(OH)2D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Serum folic acid and fexofenadine concentrations were quantified with a chemiluminescence immunoassay and LC-MS/MS, respectively. Pharmacokinetics were compared between periods with standard bioequivalence approaches.
  
  
  RESULTS
  While geometric mean folic acid AUC0-2h, which mainly reflects absorption, was 0.403 and 0.414 mg/L·h before and after the vitamin D3 course (geometric mean ratio (GMR), 1.027; 90 % confidence interval (90 % CI), 0.788-1.340), the geometric mean fexofenadine AUC0-2h was 1.932 and 2.761 mg/L·h, respectively (GMR, 1.429; 90 % CI, 0.890-2.294). PCFT- and OATP1A2-mRNA expressions in duodenal biopsies were essentially unchanged.
  
  
  CONCLUSIONS
  No significant changes in folic acid and fexofenadine absorption were observed after a 10-day course of 1,25(OH)2D3 in humans in vivo. This study underlines the importance of confirming in vitro findings in vivo in humans.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gubler
authors.affiliation: Department of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zürich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Spanaus
authors.affiliation: XenoGesis Ltd, Nottingham, UK.
authors.forename: Manfred G
authors.initials: MG
authors.lastname: Ismair
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Claro da Silva
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland. alexander.jetter@usz.ch.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000284:Administration, Oral; D000328:Adult; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D058979:Proton-Coupled Folate Transporter / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005492:Folic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D016593:Terfenadine; D014807:Vitamin D; C505058:SLC46A1 protein, human; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; C118756:dihydroxy-vitamin D3; C114462:multidrug resistance-associated protein 3; C093230:fexofenadine
keywords: 1,25-dihydroxyvitamin D3; Absorption; Fexofenadine; Folic acid; OATP1A2; PCFT