A multi-system approach assessing the interaction of anticonvulsants with P-gp.
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 r...
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064854&type=printable |
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| author | David Dickens Siti R Yusof N Joan Abbott Babette Weksler Ignacio A Romero Pierre-Olivier Couraud Ana Alfirevic Munir Pirmohamed Andrew Owen |
| author_facet | David Dickens Siti R Yusof N Joan Abbott Babette Weksler Ignacio A Romero Pierre-Olivier Couraud Ana Alfirevic Munir Pirmohamed Andrew Owen |
| author_sort | David Dickens |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-353c5f3c8e394cd9b9b95d3bc1e82cab |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-353c5f3c8e394cd9b9b95d3bc1e82cab2025-08-20T03:26:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6485410.1371/journal.pone.0064854A multi-system approach assessing the interaction of anticonvulsants with P-gp.David DickensSiti R YusofN Joan AbbottBabette WekslerIgnacio A RomeroPierre-Olivier CouraudAna AlfirevicMunir PirmohamedAndrew Owen30% 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064854&type=printable |
| spellingShingle | David Dickens Siti R Yusof N Joan Abbott Babette Weksler Ignacio A Romero Pierre-Olivier Couraud Ana Alfirevic Munir Pirmohamed Andrew Owen A multi-system approach assessing the interaction of anticonvulsants with P-gp. PLoS ONE |
| title | A multi-system approach assessing the interaction of anticonvulsants with P-gp. |
| title_full | A multi-system approach assessing the interaction of anticonvulsants with P-gp. |
| title_fullStr | A multi-system approach assessing the interaction of anticonvulsants with P-gp. |
| title_full_unstemmed | A multi-system approach assessing the interaction of anticonvulsants with P-gp. |
| title_short | A multi-system approach assessing the interaction of anticonvulsants with P-gp. |
| title_sort | multi system approach assessing the interaction of anticonvulsants with p gp |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064854&type=printable |
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