Vitamin D receptor activation induces P-glycoprotein and increases brain efflux of quinidine: an intracerebral microdialysis study in conscious rats.
Pharm Res
; 32(3): 1128-40, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25319098
ABSTRACT
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 bloodplasma 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinidina
/
Calcitriol
/
Permeabilidade Capilar
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Barreira Hematoencefálica
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Receptores de Calcitriol
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Microdiálise
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article