Potschka Heidrun, Fedrowitz Maren, Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany.
Epilepsia. 2003 Dec;44(12):1479-86. doi: 10.1111/j.0013-9580.2003.22603.x.
Different adenosine triphosphate (ATP)-driven multidrug transporters have been described to be expressed in the luminal membrane of blood-brain barrier (BBB) endothelial cells. At this site, multidrug transporters have been suggested to restrict penetration of drugs into the brain. Increasing evidence suggests that overexpression of different multidrug transporters occurs in the region of the epileptic focus of pharmacoresistant epilepsy patients. Based on the assumption that antiepileptic drugs (AEDs) are substrates of these transporters, this overexpression may limit access of AEDs to epileptic neurons and may contribute to drug-refractoriness. In a recent study, overexpression of multidrug resistance protein 2 (ABCC2; MRP2) was reported in BBB endothelial cells of epileptic focal tissue from pharmacoresistant patients. With brain microdialysis, we recently demonstrated that the AED phenytoin is subject to transport by ABCC2 at the BBB, whereas phenobarbital does not seem to be a substrate of ABCC2.
We investigated whether ABCC2 is functionally involved in transport of the AEDs carbamazepine (CBZ), lamotrigine (LTG), and felbamate (FBM) across the BBB. The distribution of these AEDs into the brain of ABCC2-deficient TR- rats was determined.
AED concentrations in plasma and brain extracellular space of these mutant rats did not differ significantly from those of rats of the corresponding background strain. In the amygdala-kindling model of epilepsy, the anticonvulsant efficacy of LTG and FBM was comparable in both groups of rats. In contrast, CBZ exhibited a higher anticonvulsant activity in kindled ABCC2-deficient rats as compared with nonmutant rats.
In this present study, the microdialysis results gave no evidence that ABCC2 function modulates entry of CBZ, LTG, and FBM into the CNS of naïve rats. However, ABCC2 deficiency was associated with an increased anticonvulsant response of CBZ in the kindling model. Future investigations are planned to identify the underlying mechanism for this difference, clarifying whether a pharmacokinetic difference is detectable only when brain access of CBZ is compared in kindled ABCC2-deficient rats and kindled nonmutant rats, which may have an increased expression of ABCC2 in response to seizures. The data substantiate that ABCC2-deficient TR- rats are a useful tool for defining the role of ABCC2 for transport of AEDs, and give evidence that the use of kindled TR- rats may provide important supplementary information.
已描述不同的三磷酸腺苷（ATP）驱动的多药转运体在血脑屏障（BBB）内皮细胞的腔膜中表达。在该部位，多药转运体被认为会限制药物进入大脑。越来越多的证据表明，耐药性癫痫患者癫痫病灶区域存在不同多药转运体的过表达。基于抗癫痫药物（AEDs）是这些转运体底物的假设，这种过表达可能会限制AEDs进入癫痫神经元，并可能导致药物难治性。在最近一项研究中，报道了耐药患者癫痫病灶组织的BBB内皮细胞中多药耐药蛋白2（ABCC2；MRP2）过表达。通过脑微透析，我们最近证明AED苯妥英在BBB处可被ABCC2转运，而苯巴比妥似乎不是ABCC2的底物。
我们研究了ABCC2是否在AEDs卡马西平（CBZ）、拉莫三嗪（LTG）和非氨酯（FBM）跨BBB转运中发挥功能作用。测定了这些AEDs在ABCC2缺陷型TR -大鼠脑内的分布情况。
这些突变大鼠血浆和脑细胞外间隙中的AED浓度与相应背景品系大鼠的浓度无显著差异。在癫痫的杏仁核点燃模型中，两组大鼠中LTG和FBM的抗惊厥效果相当。相比之下，与非突变大鼠相比，CBZ在点燃的ABCC2缺陷型大鼠中表现出更高的抗惊厥活性。
在本研究中，微透析结果未提供证据表明ABCC2功能调节CBZ、LTG和FBM进入未处理大鼠的中枢神经系统。然而，在点燃模型中，ABCC2缺陷与CBZ抗惊厥反应增强有关。计划未来进行研究以确定这种差异的潜在机制，明确是否仅在比较点燃的ABCC2缺陷型大鼠和可能因癫痫发作而ABCC2表达增加的点燃非突变大鼠中CBZ进入脑内情况时才能检测到药代动力学差异。这些数据证实ABCC2缺陷型TR -大鼠是确定ABCC2在AEDs转运中作用的有用工具，并证明使用点燃的TR -大鼠可能提供重要的补充信息。
