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Eur J Pharmacol. 2012 Sep 5;690(1-3):68-76. doi: 10.1016/j.ejphar.2012.06.032. Epub 2012 Jun 30.

Influence of P-glycoprotein on brucine transport at the in vitro blood-brain barrier.

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  • 1Institute of Clinical Pharmacy & Pharmacology, The Second Xiangya Hospital of Central South University, Changsha 410011, PR China.

Abstract

Brucine is a central agonist that can pass through the blood-brain barrier (BBB). The goal of this study is to examine whether brucine is one of the substrates of the drug transporter P-glycoprotein (P-gp) and to examine the effects of P-gp on the brucine transport at the in vitro BBB model. The P-gp ATPase assay was utilized to investigate the in vitro affinity of P-gp to brucine. Results suggested that K(m) of brucine (11.4 μmol/l) was smaller than the positive control, verapamil (16.4 μmol/l). In this study, we developed an in vitro BBB model, comprising a co-culture of primary rat brain microvessel endothelial cells and astrocytes for the transport study. The validated model was correct and available. Transendothelial electrical resistance reached (283.78 ± 18.85) Ω cm(2). The model displayed limited permeability to fluorescein sodium and [(125)I]albumin, with the apparent permeability coefficient Papp of (10.36 ± 0.86) × 10(-6) cm/s and (6.00 ± 0.78) × 10(-6)cm/s, respectively. The quantity of the bidirectional transport of brucine was determined by ultra-performance liquid chromatography-tandem mass spectrometry. In the absence of verapamil, the transport of brucine from basolateral compartment to apical compartment (BL-AP) was higher than from AP to BL at low, middle, and high concentrations (P<0.05). The excretion rate was 1.32, 1.56, and 1.54, respectively. However, following exposure to verapamil, the excretion rate at three different concentrations was decreased (P<0.05). All the results suggest that P-gp prevented brucine from passing through the in vitro BBB model.

PMID:
22749978
DOI:
10.1016/j.ejphar.2012.06.032
[PubMed - indexed for MEDLINE]
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