Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry-A Study in Rats Subjected to Status Epilepticus by Kainate
Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry-A Study in Rats Subjected to Status Epilepticus by Kainate
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DOI：
10.1208/s12248-011-9318-1
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发表时间：
2012-03-01
期刊：
影响因子：
4.5
通讯作者：
de lange, Elizabeth C.
中科院分区：
文献类型：
--
作者：
Syvanen, Stina;Schenke, Maarten;de lange, Elizabeth C.
本研究旨在研究奎尼丁微透析对卡因酸盐诱导癫痫持续状态（SE）后脑p -糖蛋白功能的潜在变化。给大鼠注射10或20 mg/kg奎尼丁，注射时间为30 min或4 h。注射开始后7 h，测定血浆、脑外细胞液（brain ECF）和实验结束时奎尼丁脑总浓度。研究前给药tariquar （15 mg/kg，在奎尼丁输注前30 min给药）对奎尼丁脑分布的影响。在盐处理的大鼠中重复该方法。用群体模型（NONMEM）分析奎尼丁动力学。奎尼丁微透析分析清楚地显示，预先给药塔奎德可改变p -糖蛋白功能，导致脑ECF增加7.2倍，脑奎尼丁总浓度增加40倍。然而，单独使用盐酸盐处理后，奎尼丁通过血脑屏障的转运没有发现差异，但盐酸盐处理大鼠的奎尼丁脑总浓度较低，但脑ECF浓度高于盐处理大鼠。本研究并未为SE诱导1周后血脑屏障p -糖蛋白功能改变的假设提供证据，而是提示p -糖蛋白功能可能在脑实质水平发生改变。
This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood-brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood-brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level.