CNS 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变化很大。 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 这个项目的目的是调查这种低和可变的原因， VPA进入大脑 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- delta 2-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

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.