Vitamin D Receptor Activation Induces P-Glycoprotein and Increases Brain Efflux of Quinidine:An Intracerebral Microdialysis Study in Conscious Rats

• Published in: Pharmaceutical research Vol. 32; no. 3; pp. 1128 - 1140
• Main Authors: Durk, Matthew R., Fan, Jianghong, Sun, Huadong, Yang, Yingbo, Pang, Henrianna, Pang, K. Sandy, de Lannoy, Inés A. M.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.03.2015; Springer Nature B.V
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biochemistry; Biological Transport; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-brain barrier; 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; Glycoproteins; Male; Medical Law; Microdialysis; Microsomes, Liver - enzymology; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Protein Binding; Quinidine - blood; Quinidine - metabolism; Rats, Sprague-Dawley; Receptors, Calcitriol - agonists; Receptors, Calcitriol - metabolism; Research Paper; Rodents; Up-Regulation; Vitamin D; P-glycoprotein; vitamin D receptor; blood–brain barrier; microdialysis
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1524-y

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 D 3 [1,25(OH) 2 D 3 ] (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) 2 D 3 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) 2 D 3 , 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, K ECF/P,uu and K ECF/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.