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

TY - JOUR

T1 - A Multi-System Approach Assessing the Interaction of Anticonvulsants with P-gp

AU - Dickens, David

AU - Yusof, Siti R.

AU - Abbott, N. Joan

AU - Weksler, Babette

AU - Romero, Ignacio A.

AU - Couraud, Pierre-Olivier

AU - Alfirevic, Ana

AU - Pirmohamed, Munir

AU - Owen, Andrew

PY - 2013/5/31

Y1 - 2013/5/31

N2 - 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 (P-app) 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.

AB - 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 (P-app) 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.

KW - BLOOD-BRAIN-BARRIER

KW - GLYCOPROTEIN-MEDIATED EFFLUX

KW - ENDOTHELIAL-CELL LINE

KW - IN-VITRO

KW - ANTIEPILEPTIC DRUGS

KW - MULTIDRUG-RESISTANCE

KW - REFRACTORY EPILEPSY

KW - CLINICAL-SIGNIFICANCE

KW - PROTEASE INHIBITORS

KW - GENE-EXPRESSION

U2 - 10.1371/journal.pone.0064854

DO - 10.1371/journal.pone.0064854

M3 - Article

SN - 1932-6203

VL - 8

JO - PL o S One

JF - PL o S One

IS - 5

M1 - 64854

ER -