Artikel
Induction of PCFT and OATP1A2 via vitamin D receptor activation in vitro is not confirmed in vivo in healthy volunteers after a 10-days treatment with 1,25-dihydroxyvitamin D3
Suche in Medline nach
Autoren
-
I. Marti
- University Hospital Zurich, Department of Clinical Pharmacology and Toxicology – Zürich, Schweiz
-
T. Claro da Silva
- University Hospital Zurich, Department of Clinical Pharmacology and Toxicology – Zürich, Schweiz
-
K. Spanaus
- University Hospital Zurich, Institute for Clinical Chemistry – Zürich, Schweiz
-
C. Gubler
- University Hospital Zurich, Department of Gastroenterology and Hepatology – Zürich, Schweiz
-
G. A. Kullak-Ublick
- University Hospital Zurich, Department of Clinical Pharmacology and Toxicology – Zürich, Schweiz
-
A. Jetter
- University Hospital Zurich, Department of Clinical Pharmacology and Toxicology – Zürich, Schweiz
| Veröffentlicht: | 25. September 2014 |
|---|
Gliederung
Text
Aim: In humans, intestinal uptake of folic acid is mainly mediated by the proton-coupled folate transporter PCFT. In Caco-2 cells, the cellular uptake of folate via PCFT can be increased between 2- and 4-fold by a three-day treatment with 1,25-dihydroxyvitamin D3. Additionally, mRNA content and protein expression of the intestinal transporter OATP1A2 were increased up to 9-fold with 1,25-dihydroxyvitamin D3. We therefore investigated whether 1,25-dihydroxyvitamin D3 intake in humans leads to increased intestinal expression and function of these 2 transporters.
Method: Ten healthy volunteers (6 women, 4 men) received a single oral dose of 5 mg folic acid once before and once together with the last oral dose of a ten-day course of 0.5 µg 1,25-dihydroxyvitamin D3 daily. 120 mg of the OATP1A2 substrate fexofenadine were taken in orally twice: one day before the first folic acid intake, and again on the ninth day of 1,25-dihydroxyvitamin D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Plasma folic acid concentrations up to 6 h after intake were quantified with a chemiluminescence immunoassay. Noncompartimental pharmacokinetic parameters were compared between periods with a standard bioequivalence approach.
Results: All volunteers completed the study. Only mild and transient adverse events were reported. Geometric mean folic acid exposure up to 6 h postdose (AUC0-6h) increased non significantly from 1.466 to 1.507 mg/L*h (geometric mean ratio GMR 1.0283, 90% confidence interval CI: 0.8637–1.2243). The Cmax and AUC0-2h values, which mainly reflect absorption, also did not change significantly. PCFT- and OATP1A2-mRNA expressions in biopsy samples were essentially unchanged after the ten-day course of 1,25-dihydroxyvitamin D3.
Conclusion: Although there is in vitro evidence that intestinal folate uptake can be increased by 1,25-dihydroxyvitamin D3 via PCFT induction, and that OATP1A2 is also inducible by this vitamin, a ten-day course of 1,25-dihydroxyvitamin D3 did not lead to higher expressions of PCFT or OATP1A2, or to increases in folic acid absorption in humans.
