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


Eur J Pharmacol. 2012 Jun 29;


Authors: Xu DH, Yan M, Li HD, Fang PF, Liu YW


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 (11.4µmol/l) was smaller than the positive control, verapamil (16.4µmol/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) Ωcm(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-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 [PubMed - as supplied by publisher]