Differences in the transport of the antiepileptic drugs phenytoin, levetiracetarn and carbamazepine by human and mouse P-glycoprotein
Differences in the transport of the antiepileptic drugs phenytoin, levetiracetarn and carbamazepine by human and mouse P-glycoprotein
复制标题
DOI：
10.1016/j.neuropharm.2006.07.038
复制
发表时间：
2007-02-01
影响因子：
4.7
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
--
作者：
Baltes, Steffen;Gastens, Alexandra M.;Loescher, Wolfgang
鉴于P-糖蛋白（Pgp）和其他药物外排转运蛋白对药物分布和耐药性的重要作用，鉴定作为Pgp介导的转运底物的化合物是药物发现和开发的关键问题之一，特别是对于作用于中枢神经系统的化合物。 Pgp 转染肾细胞系的体外转运测定广泛用于评估化合物作为 Pgp 底物或抑制剂的潜力。此外，此类细胞系也经常被用作血脑屏障（BBB）劳动密集型体外或体内模型的替代品。 BBB 处 Pgp 或多药耐药蛋白 (MRP) 家族成员的过度表达与癫痫患者抗癫痫药物 (AED) 耐药的机制有关。因此，了解哪些 AED 是 Pgp 或 MRP 的底物非常重要。在本研究中，我们使用单层极化 MDCKII 狗肾或 LLC-PK1 猪肾细胞，转染含有人 MDR1、MRP2 或小鼠 mdr1a 和 mdr1b 序列的 cDNA，以测量 AED 的定向转运。环孢素 A (CsA) 和长春花碱分别用作 Pgp 和 MRP2 的参考标准品。 AED 苯妥英和左乙拉西坦由小鼠而非人 Pgp 定向转运，而 CsA 则由两种类型的 Pgp 转运。卡马西平不被任何类型的 Pgp 转运，也不抑制 CsA 的转运。与长春花碱相反，在转染的肾细胞中，MRP2 不会转运任何 AED。数据表明，对于某些 AED，Pgp 的底物识别或转运功效在人类和小鼠之间存在差异。这种物种差异当然不限于人类和小鼠，可以至少部分解释先前报道的不同物种制剂中 Pgp 转运 AED 的争议数据。然而，由于Pgp或MRP2等外排转运蛋白的转运功效不仅在物种之间而且在组织之间也存在差异，因此目前的数据并不排除所检查的AED是人类BBB处的Pgp或MRP2的弱底物。 (c) 2006 Elsevier Ltd. 保留所有权利。
In view of the important role of P-glycoprotein (Pgp) and other drug efflux transporters for drug distribution and resistance, the identification of compounds as substrates of Pgp-mediated transport is one of the key issues in drug discovery and development, particularly for compounds acting on the central nervous system. In vitro transport assays with Pgp-transfected kidney cell lines are widely used to evaluate the potential of compounds to act as Pgp substrates or inhibitors. Furthermore, such cell lines are also frequently utilized as a substitute for more labor-intensive in vitro or in vivo models of the blood-brain barrier (BBB). Overexpression of Pgp or members of the multidrug resistance protein (MRP) family at the BBB has been implicated in the mechanisms underlying resistance to antiepileptic drugs (AEDs) in patients with epilepsy. Therefore, it is important to know which AEDs are substrates for Pgp or MRPs. In the present study, we used monolayers of polarized MDCKII dog kidney or LLC-PK1 pig kidney cells transfected with cDNA containing either human MDR1, MRP2 or mouse mdr1a and mdr1b sequences to measure the directional transport of AEDs. Cyclosporin A (CsA) and vinblastine were used as reference standards for Pgp and MRP2, respectively. The AEDs phenytoin and levetiracetam were directionally transported by mouse but not human Pgp, whereas CsA was transported by both types of Pgp. Carbamazepine was not transported by any type of Pgp and did not inhibit the transport of CsA. In contrast to vinblastine, none of the AEDs was transported by MRP2 in transfected kidney cells. The data indicate that substrate recognition or transport efficacy by Pgp differs between human and mouse for certain AEDs. Such species differences, which are certainly not restricted to human and mouse, may explain, at least in part, the controversial data which have been previously reported for AED transport by Pgp in preparations from different species. However, because transport efficacy of efflux transporters such as Pgp or MRP2 may not only differ between species but also between tissues, the present data do not exclude that the AEDs examined are weak substrates of Pgp or MRP2 at the human BBB. (c) 2006 Elsevier Ltd. All rights reserved.