Antiepileptic Drug Transport—Of Mice and Men
Authors: Sills Graeme J. 
Published: February 2008

Differences in the Transport of the Antiepileptic Drugs Phenytoin, Levetiracetam and Carbamazepine by Human and Mouse P-Glycoprotein. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W. Neuropharmacology 2007;52(2):333–346. In view of the important role of P-glycoprotein (P-gp) and other drug efflux transporters for drug distribution and resistance, the identification of compounds as substrates of P-gp-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 P-gp-transfected kidney cell lines are widely used to evaluate the potential of compounds to act as P-gp 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 P-gp 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 P-gp 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 P-gp and MRP2, respectively. The AEDs phenytoin and levetiracetam were directionally transported by mouse but not human P-gp, whereas CsA was transported by both types of P-gp. Carbamazepine was not transported by any type of P-gp 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 P-gp 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 that have been previously reported for AED transport by P-gp in preparations from different species. However, because transport efficacy of efflux transporters such as P-gp 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 P-gp or MRP2 at the human BBB.

Valproic Acid Is Not a Substrate for P-Glycoprotein or Multidrug Resistance Proteins 1 and 2 in a Number of In Vitro and In Vivo Transport Assays. Baltes S, Fedrowitz M, Tortos CL, Potschka H, Loscher W. J Pharmacol Exp Ther 2007;320(1):331–343. The antiepileptic drug valproic acid (VPA) is widely used in the treatment of epilepsy, bipolar disorders, and migraine. However, rather high doses are required for the clinical effects of VPA, which is due to its relatively inefficient delivery to the brain. The poor brain distribution of VPA is thought to reflect an asymmetric transport system at the blood–brain barrier (BBB). Based on recent data from in vitro experiments, multidrug resistance proteins (MRPs) have been proposed to be involved in the efflux transport of VPA at the BBB. In the present study, we used different experimental in vitro and in vivo strategies to evaluate whether VPA is a substrate for MRPs or the efflux transporter P-glycoprotein (P-gp). In contrast to known P-gp or MRP substrates, such as cyclosporin A or vinblastine, no directional transport of VPA was observed in cell monolayer efflux assays using the kidney cell lines Madin Darby canine kidney II and LLC-PK1, which had been transfected with either human or mouse cDNAs for the genes encoding P-gp, MRP1, or MRP2. Likewise, no indication for efflux transport of VPA was obtained in a rat microdialysis model, using inhibitors of either P-gp or MRPs. Furthermore, a significant role of MRP2 in brain efflux of VPA was excluded by using MRP2-deficient rats. Our data do not support the hypothesis that MRP1 or MRP2 is involved in the efflux of VPA from the brain. Thus, the molecular identity of the putative transporter(s) mediating the active efflux of VPA from the brain remains to be elucidated.