Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease.
Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease.
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DOI：
10.1038/srep09000
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发表时间：
2015-03-11
影响因子：
4.6
通讯作者：
Ho PC
中科院分区：
文献类型：
--
作者：
Chang KL;Pee HN;Yang S;Ho PC
吡格列酮目前正在进行治疗阿尔茨海默病（AD）的临床试验。然而，较差的脑渗透性仍然是开发用于此类预期临床用途的药物的障碍。在这项研究中，我们证明，P-糖蛋白（P-gp）的抑制显着增加吡格列酮的脑渗透，而乳腺癌耐药蛋白（BCRP）的抑制作用很小。我们还研究了吡格列酮在脑中摄取的立体选择性。当小鼠接受外消旋吡格列酮给药时，脑组织中（+）-吡格列酮的浓度比（-）-吡格列酮高46.6%，血浆中（-）-吡格列酮的浓度比（-）-吡格列酮低67.7%。与同等剂量的外消旋吡格列酮相比，纯（+）-吡格列酮给药小鼠导致脑暴露水平增加76%。在体外AD模型中，纯（+）-吡格列酮也显示出与外消旋吡格列酮具有相当的降低淀粉样蛋白的能力。这些结果表明，P-gp可能作为立体选择性屏障，以防止吡格列酮进入脑。用（+）-吡格列酮代替外消旋混合物给药可能导致吡格列酮的脑暴露水平更高，从而可能改善吡格列酮治疗AD的开发。
Pioglitazone is currently undergoing clinical trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clinical uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concentration of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equivalent dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixture may result in higher levels of brain exposure to pioglitazone, thus potentially improving the development of pioglitazone treatment of AD.