Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
J Neurochem. 2013 Nov;127(3):342-52. doi: 10.1111/jnc.12344. Epub 2013 Jul 15.
Intracerebral microdialysis was utilized to investigate the effect of P-glycoprotein (a drug efflux transporter) induction at the mouse blood-brain barrier (BBB) on brain extracellular fluid concentrations of quinidine, an established substrate of P-glycoprotein. Induction was achieved by treating male CD-1 mice for 3 days with 5 mg/kg/day dexamethasone (DEX), a ligand of the nuclear receptor, pregnane X receptor, and a P-glycoprotein inducer. Tandem liquid chromatography mass spectrometric method was used to quantify analytes in dialysate, blood and plasma. P-glycoprotein, pregnane X receptor and Cyp3a11 (metabolizing enzyme for quinidine) protein expression in capillaries and brain homogenates was measured by immunoblot analysis. Following quinidine i.v. administration, the average ratio of unbound quinidine concentrations in brain extracellular fluid (determined from dialysate samples) to plasma at steady state (375-495 min) or Kp, uu, ECF /Plasma in the DEX-treated animals was 2.5-fold lower compared with vehicle-treated animals. In DEX-treated animals, P-glycoprotein expression in brain capillaries was 1.5-fold higher compared with vehicle-treated animals while Cyp3a11 expression in brain capillaries was not significantly different between the two groups. These data demonstrate that P-gp induction mediated by DEX at the BBB can significantly reduce quinidine brain extracellular fluid concentrations by decreasing its brain permeability and further suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible. Applying microdialysis, distribution of quinidine, a P-gp substrate, in mouse brain extracellular fluid (ECF) was investigated following ligand-mediated P-glycoprotein (P-gp) induction at the blood-brain barrier (BBB). We demonstrated that a PXR agonist (dexamethasone) significantly up-regulated P-gp in brain capillaries and reduced quinidine brain ECF concentrations. Our data suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible.
利用脑室内微透析技术研究了 P-糖蛋白（一种药物外排转运体）在小鼠血脑屏障（BBB）中的诱导作用对奎尼丁脑细胞外液浓度的影响，奎尼丁是 P-糖蛋白的一种既定底物。诱导作用是通过用 5mg/kg/天地塞米松（DEX）处理雄性 CD-1 小鼠 3 天来实现的，DEX 是核受体孕烷 X 受体的配体，也是 P-糖蛋白诱导剂。串联液相色谱-质谱联用方法用于定量透析液、血液和血浆中的分析物。通过免疫印迹分析测量毛细血管和脑匀浆中的 P-糖蛋白、孕烷 X 受体和 Cyp3a11（奎尼丁代谢酶）蛋白表达。静脉注射奎尼丁后，DEX 处理动物稳态时（375-495 分钟）或 Kp，uu，ECF/Plasma 下脑细胞外液（通过透析液样本确定）中未结合的奎尼丁浓度与血浆的平均比值比载体处理动物低 2.5 倍。在 DEX 处理的动物中，P-糖蛋白在脑毛细血管中的表达比载体处理的动物高 1.5 倍，而两组之间 Cyp3a11 在脑毛细血管中的表达没有显著差异。这些数据表明，DEX 在 BBB 处诱导 P-gp 可通过降低其脑通透性显著降低奎尼丁脑细胞外液浓度，并进一步表明由于 BBB 处 P-gp 诱导导致的药物-药物相互作用是可能的。通过应用微透析，在血脑屏障（BBB）处经配体介导的 P-糖蛋白（P-gp）诱导后，研究了 P-gp 底物奎尼丁在小鼠脑细胞外液（ECF）中的分布。我们证明，PXR 激动剂（地塞米松）显著上调了脑毛细血管中的 P-gp，并降低了奎尼丁脑 ECF 浓度。我们的数据表明，由于 BBB 处 P-gp 诱导导致的药物-药物相互作用是可能的。
