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 抗癫痫药，VPA的抗惊厥活性相关性较差 与血浆药物浓度有关。神经外科患者的最新研究 显示，在慢性VPA治疗期间，人体内VPA的浓度 脑组织中的血药浓度明显低于血清总药物和游离药物 浓度。更重要的是稳定状态的大脑- 血清浓度比在不同个体之间差别很大。它 似乎未能证明一种清晰可定义的关系 丙戊酸临床疗效与循环血药浓度的关系 癫痫可能与异常庞大的个体间有关 药物的血-脑分配的变化。总体目标 这个项目的目的是调查这一低和可变的原因 丙戊酸在脑内的分布。我们假设(1)易位 VPA跨越血脑和血脑脊液(CSF)屏障 由内源羧酸的膜运输载体介导， (2)这些运输的生理调节存在个体差异 过程解释了观察到的VPA中枢分布的变化 患者之间，以及(3)低脑-血液浓度梯度 VPA是由于大脑和血液之间的药物传输不对称造成的。 因此，在动物模型中进行了一系列体内和体外研究 建议确定和确定假定的运输承运人的特征 VPA及其2-不饱和类似物(E)-β2-VPA。后者的化合物是 目前正在开发第二代烷酸盐类 抗惊厥药。我们将检验VPA和(E)的具体假设- Delta2-VPA通过大脑毛细血管内皮细胞穿梭 一元羧酸(MCA)转运体，它介导了 血和脑之间的酮体和乳酸。脑血管 运输研究将使用原位脑血流灌注进行 大鼠技术和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MCAS共享相同的内皮转运系统将被寻求。 脉络膜上皮细胞外流途径的作用将是 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 兔脉络丛的制备。具体地说，我们将测试 中间的支链脂肪酸由有机阴离子运输。 脉络丛刷缘膜上的交换器。信息 支链脂肪酸在中枢神经系统的转运可能有助于 制定以机制为基础的战略，以改善 烷酸盐类抗癫痫药。

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.