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CNS DELIVERY OF ALKANOATE ANTIEPILEPTICS

链烷酸盐抗癫痫药的中枢神经系统输送

基本信息

批准号：
2908382
负责人：
DANNY D SHEN
金额：
$ 8.18万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 2000-06-30
项目状态：
已结题

项目摘要

The antiepileptic drug valproic acid (VPA) is a branched-chain fatty acid with unique pharmacodynamic properties. Unlike other commonly used antiepileptics, the anticonvulsant activity of VPA is poorly correlated with plasma drug concentration. Recent studies in neurosurgical patients showed that, during chronic VPA therapy, the concentrations of VPA in human brain were much lower than either the total or unbound serum drug concentrations. More significant is the fact that the steady-state brain- to-serum concentration ratios varied widely between individuals. It appears that the failure to demonstrate a clearly definable relationship between clinical effect and circulating concentration of VPA in patients with epilepsy may be related to the unusually large interindividual variation in blood-brain partitioning of the drug. The overall objective of this project is to investigate the cause of this low and variable distribution of VPA into brain. We hypothesize that (1) the translocation of VPA across blood-brain and blood-cerebrospinal fluid (CSF) barriers is mediated by membrane transport carriers for endogenous carboxylic acids, (2) individual differences in the physiologic regulation of these transport processes accounts for the observed variation in CNS distribution of VPA between patients, and (3) the low brain-to-blood concentration gradient of VPA is due to an asymmetry in drug transport between brain and blood. Thus, a series of in vivo and in vitro studies in animal models are proposed to identify and characterize the putative transport carriers for VPA and its 2-unsaturated analog (E)-delta2-VPA. The latter compound is currently under development as a second generation alkanoate anticonvulsant. We will test the specific hypothesis that VPA and (E)- delta2-VPA are shuttled across the brain capillary endothelium by the monocarboxylic acid (MCA) transporter, which mediates the exchange of ketone bodies and lactate between blood and brain. Cerebrovascular transport studies will be performed using the in situ brain perfusion technique in rats and the in vitro bovine brain microvessel endothelial cell culture model. Evidence that the branched-chain fatty acids and endogenous MCAs share the same endothelial transport system will be sought. The contribution of an efflux pathway at the choroidal epithelium will be investigated by in vitro uptake studies with isolated rabbit choroid plexus and by transepithelial transport studies with an in situ lateral ventricle choroid plexus preparation in the rabbit. Specifically, we will test if the medium, branched-chain fatty acids are transported by the organic anion exchanger at the brush-border membrane of the choroid plexus. Information on the CNS transport of branched-chain fatty acids may be useful in developing mechanism-based strategies for improving the brain delivery of alkanoate antiepileptics.

抗癫痫药物丙戊酸（VPA）是一种支链脂肪酸具有独特的药效学特性。不同于其他常用的与抗癫痫药相比，VPA的抗惊厥活性相关性较差血浆药物浓度。神经外科患者的最新研究显示，在慢性VPA治疗期间，人体中VPA的浓度脑内的药物浓度远低于总的或未结合的血清药物浓度浓度的更重要的是稳态大脑- 与血清的浓度比在个体之间差异很大。它看来，未能证明一个明确界定的关系，患者中VPA的临床效果和循环浓度之间的关系癫痫可能与异常大的个体间药物血脑分配的变化。总体目标该项目的目的是调查这种低水平和可变性的原因丙戊酸盐分布到大脑中。我们假设（1）易位 VPA穿过血脑和血脑脊液（CSF）屏障的能力由内源性羧酸的膜转运载体介导， (2)这些运输的生理调节的个体差异过程解释了观察到的VPA CNS分布变化患者之间，和（3）低脑-血浓度梯度 VPA是由于大脑和血液之间药物转运的不对称性。因此，在动物模型中进行了一系列体内和体外研究。建议确定和描述假定的运输载体， VPA及其2-不饱和类似物（E）-δ 2-VPA。后一种化合物是目前正在开发的第二代链烷酸酯抗惊厥药我们将测试VPA和（E）的特定假设- delta2-VPA通过脑毛细血管内皮穿梭，一元羧酸（MCA）转运蛋白，介导的交换，酮体和乳酸盐。脑血管将使用原位脑灌注进行转运研究体外牛脑微血管内皮细胞细胞培养模型有证据表明，支链脂肪酸和内源性MCA共享相同的内皮转运系统。脉络膜上皮的外排途径的贡献将是通过离体兔脉络丛的体外摄取研究并通过原位侧脑室的跨上皮转运研究家兔脉络丛制备。具体来说，我们将测试中等支链脂肪酸由有机阴离子运输在脉络丛刷状缘膜的交换器。信息对CNS转运支链脂肪酸的作用可能有助于发展机制为基础的战略，以改善大脑交付的链烷酸酯抗癫痫药