Differences in the transport of the antiepileptic drugs phenytoin, levetiracetarn and carbamazepine by human and mouse P-glycoprotein

被引:181
作者
Baltes, Steffen
Gastens, Alexandra M.
Fedrowitz, Maren
Potschka, Heidrun
Kaever, Volkhard
Loescher, Wolfgang
机构
[1] Univ Vet Med Hannover, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany
[2] Hannover Med Sch, Inst Pharmacol, D-3000 Hannover, Germany
关键词
multidrug transporters; phenytoin; levetiracetam; carbamazepine; cyclosporin A; blood-brain barrier;
D O I
10.1016/j.neuropharm.2006.07.038
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:333 / 346
页数:14
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