In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: Insights into the mechanisms of pharmacoresistance
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- 作者：Emily Oby ; Silvio Caccia ; Annamaria Vezzani ; Gabriel Moeddel ; Kerri Hallene ; Giovanna Guiso ; Tamer Said ; William Bingaman ; Nicola Marchi ; Christoph Baumgartner et al.
- 关键词：Drug transport ; Cortical dysplasia ; Brain development ; P-glycoprotein ; Pharmacokinetic
- 刊名：Brain Research
- 出版年：2006
- 出版时间：1 May 2006
- 年：2006
- 卷：1086
- 期：1
- 页码：201-213
- 全文大小：503 K
文摘
Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15–34 μM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg2+-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40 % . Similar results were obtained for PHT. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.