The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins.
OBJECTIVE
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.
Luna-Tortós
Carlos
C
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany.
Rambeck
Bernhard
B
Jürgens
Uwe H
UH
Löscher
Wolfgang
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism; D002460:Cell Line; D004827:Epilepsy / Q000188:drug therapy; D005632:Fructose / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D000077236:Topiramate
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D005632:Fructose; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; D000077236:Topiramate