A Multi-System Approach Assessing the Interaction of Anticonvulsants with P-gp

David Dickens,Andrew Owen,Babette Weksler,Pierre-Olivier Couraud,Munir Pirmohamed,Ana Alfirevic,Ignacio A Romero,Siti R Yusof,N Joan Abbott,Valentin Ceña

doi:10.1371/journal.pone.0064854

Abstract

30% of epilepsy patients receiving antiepileptic drugs (AEDs) are not fully controlled by therapy. The drug transporter hypothesis for refractory epilepsy proposes that P-gp is over expressed at the epileptic focus with a role of P-gp in extruding AEDs from the brain. However, there is controversy regarding whether all AEDs are substrates for this transporter. Our aim was to investigate transport of phenytoin, lamotrigine and carbamazepine by using seven in-vitro transport models. Uptake assays in CEM/VBL cell lines, oocytes expressing human P-gp and an immortalised human brain endothelial cell line (hCMEC/D3) were carried out. Concentration equilibrium transport assays were performed in Caco-2, MDCKII ±P-gp and LLC-PK1±P-gp in the absence or presence of tariquidar, an inhibitor of P-gp. Finally, primary porcine brain endothelial cells were used to determine the apparent permeability (Papp) of the three AEDs in the absence or presence of P-gp inhibitors. We detected weak transport of phenytoin in two of the transport systems (MDCK and LLC-PK1 cells transfected with human P-gp) but not in the remaining five. No P-gp interaction was observed for lamotrigine or carbamazepine in any of the seven validated in-vitro transport models. Neither lamotrigine nor carbamazepine was a substrate for P-gp in any of the model systems tested. Our data suggest that P-gp is unlikely to contribute to the pathogenesis of refractory epilepsy through transport of carbamazepine or lamotrigine.

Highlights

The transport hypothesis proposes that over-expression of P-gp (Pglycoprotein, ABCB1, MDR1) at the blood-brain barrier (BBB) may increase drug efflux and limit access of antiepileptic drugs (AEDs) to the epileptic focus [2]
This has led to the hypothesis that upregulation of P-gp at the epileptic focus of refractory epilepsy patients plays a causal role in the lack of drug response by reducing the concentrations of AEDs at the epileptic focus
The hypothesis that P-gp has a causal role in refractory epilepsy remains unproven, but recent data have confirmed that P-gp protein expression is up-regulated at the epileptic focus in refractory patients [4]

Summary

Introduction

The key finding of high levels of P-gp expression in temporal lobe specimens has supported its role in the pathogenesis of refractory epilepsy [3] This has led to the hypothesis that upregulation of P-gp at the epileptic focus of refractory epilepsy patients plays a causal role in the lack of drug response by reducing the concentrations of AEDs at the epileptic focus. This is an active area of clinical research as a possible target for treatment of refractory epilepsy. The hypothesis that P-gp has a causal role in refractory epilepsy remains unproven, but recent data have confirmed that P-gp protein expression is up-regulated at the epileptic focus in refractory patients [4]

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Conclusion