PURPOSE: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs).In this respect, it is important to know which AEDs are substrates for such drug transporters in humans. METHODS: In the present study, we used polarized kidney cell lines (LLC, MDCK) transfected with human drug transporters (Pgp, MRP1, MRP2 or MRP5) to evaluate whether the AED topiramate is a substrate for any of these transporters. Known Pgp and MRP substrates were used for comparison. RESULTS: Basolateral-to-apical transport of topiramate, which could be counteracted with the Pgp inhibitor, tariquidar, was determined in Pgp overexpressing LLC cells, whereas topiramate was not transported by any of the MRPs. A comparison with previous experiments in the same transport assay showed that topiramate exhibited the most pronounced Pgp-mediated efflux transport among the AEDS that have been studied as yet. CONCLUSIONS: Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.
PURPOSE: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs).In this respect, it is important to know which AEDs are substrates for such drug transporters in humans. METHODS: In the present study, we used polarized kidney cell lines (LLC, MDCK) transfected with human drug transporters (Pgp, MRP1, MRP2 or MRP5) to evaluate whether the AED topiramate is a substrate for any of these transporters. Known Pgp and MRP substrates were used for comparison. RESULTS: Basolateral-to-apical transport of topiramate, which could be counteracted with the Pgp inhibitor, tariquidar, was determined in Pgp overexpressing LLC cells, whereas topiramate was not transported by any of the MRPs. A comparison with previous experiments in the same transport assay showed that topiramate exhibited the most pronounced Pgp-mediated efflux transport among the AEDS that have been studied as yet. CONCLUSIONS: Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.
Authors: M Yamazaki; W E Neway; T Ohe; I Chen; J F Rowe; J H Hochman; M Chiba; J H Lin Journal: J Pharmacol Exp Ther Date: 2001-03 Impact factor: 4.030
Authors: S M Dombrowski; S Y Desai; M Marroni; L Cucullo; K Goodrich; W Bingaman; M R Mayberg; L Bengez; D Janigro Journal: Epilepsia Date: 2001-12 Impact factor: 5.864
Authors: Bernhard Rambeck; Uwe H Jürgens; Theodor W May; Heinz Wolfgang Pannek; Friedrich Behne; Alois Ebner; Ali Gorji; Heidrun Straub; Erwin-Josef Speckmann; Bernd Pohlmann-Eden; Wolfgang Löscher Journal: Epilepsia Date: 2006-04 Impact factor: 5.864
Authors: Stina Syvänen; Gert Luurtsema; Carla F M Molthoff; Albert D Windhorst; Marc C Huisman; Adriaan A Lammertsma; Rob A Voskuyl; Elizabeth C de Lange Journal: BMC Med Imaging Date: 2011-01-03 Impact factor: 1.930