The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

被引:87
作者
Karssen, AM
Meijer, OC
van der Sandt, ICJ
De Boer, AG
De Lange, ECM
De Kloet, ER
机构
[1] Leiden Univ, Med Ctr, Div Med Pharmacol, Leiden Amsterdam Ctr Drug Res, NL-2300 RA Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, NL-2300 RA Leiden, Netherlands
关键词
D O I
10.1677/joe.0.1750251
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone. In vivo, a tracer dose of [H-3]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a (-/-) nice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of [3H]prednisolone. Human Pgp does not transport all steroids, as cortexolone was not transported at all and aldosterone was only weakly transported. The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.
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页码:251 / 260
页数:10
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