Vitamin D receptor activation induces P-glycoprotein and increases brain efflux of quinidine: an intracerebral microdialysis study in conscious rats

Pharm Res. 2015 Mar;32(3):1128-40. doi: 10.1007/s11095-014-1524-y. Epub 2014 Oct 16.


Purpose: Since the vitamin D receptor (VDR) was found to up-regulate cerebral P-glycoprotein expression in vitro and in mice, we extend our findings to rats by assessing the effect of rat Vdr activation on brain efflux of quinidine, a P-gp substrate that is eliminated primarily by cytochrome P450 3a.

Methods: We treated rats with vehicle or the active VDR ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] (4.8 or 6.4 nmol/kg i.p. every 2nd day × 4) and examined P-gp expression and cerebral quinidine disposition via microdialysis in control and treatment studies conducted longitudinally in the same rat.

Results: The 6.4 nmol/kg 1,25(OH)2D3 dose increased cerebral P-gp expression 1.75-fold whereas hepatic Cyp3a remained unchanged. Although there was no change in systemic clearance elicited by 1,25(OH)2D3, brain extracellular fluid quinidine concentrations were lower in treated rats. We noted that insertion of indwelling catheters increased plasma protein binding of quinidine and serial sampling decreased the blood:plasma concentration ratio, factors that alter distribution ratios in microdialysis studies. After appropriate correction, KECF/P,uu and KECF/B,uu, or ratios of quinidine unbound concentrations in brain extracellular fluid to plasma or blood at steady-state, were more than halved.

Conclusion: We demonstrate that VDR activation increases cerebral P-gp expression and delimits brain penetration of P-gp substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Biological Transport
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Calcitriol / pharmacology*
  • Capillary Permeability / drug effects*
  • Consciousness
  • Cytochrome P-450 CYP3A / metabolism
  • Dose-Response Relationship, Drug
  • Male
  • Microdialysis*
  • Microsomes, Liver / enzymology
  • Protein Binding
  • Quinidine / blood
  • Quinidine / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, Calcitriol / agonists*
  • Receptors, Calcitriol / metabolism
  • Up-Regulation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Receptors, Calcitriol
  • Cytochrome P-450 CYP3A
  • Calcitriol
  • Quinidine