JPET #54197; page 1 Interaction of Antiepileptic Drugs with Human P-Glycoprotein in Vitro

About one-third of the epilepsy patients are resistant to treatment with antiepileptic drugs (AEDs). This refractoriness is not fully understood but is thought to be attributed to overexpression of multidrug transporters at the blood-brain barrier (BBB), particularly Pglycoprotein (Pgp). In certain cases pharmacoresistance can be overcome by add-on therapy, raising the question of whether the co-administered drugs act as inhibitors of Pgp. Indeed several AEDs are substrates and to some extent also inducers of Pgp. So far, nothing is known about possible Pgp inhibitory activities of AEDs. Therefore, we investigated whether AEDs commonly used in monoor add-on-therapy inhibit Pgp using a calcein acetoxymethylester (calcein-AM) uptake assay with L-MDR1 cells and primary porcine brain capillary endothelial cells (pBCECs) as well as confocal laser-scanning microscopy with L-MDR1 cells and bodipy-verapamil as Pgp substrate. In the calcein assay only carbamazepine inhibited Pgp, which was confirmed in confocal laser-scanning microscopy. In this assay, also phenytoin, lamotrigine, and valproate revealed Pgp inhibitory potency. Because Pgp inhibition by AEDs appeared at significantly higher concentrations than that of well-known inhibitors and because the effective concentrations exceeded therapeutic AED plasma concentrations, Pgp inhibition appears not to be of clinical relevance at least in antiepileptic monotherapy. However, it is possible that this inhibition may contribute to the effectiveness of certain add-on therapies. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on September 3, 2003 as DOI: 10.1124/jpet.103.054197 at A PE T Jornals on July 9, 2017 jpet.asjournals.org D ow nladed from