Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats.
OBJECTIVE
Overexpression of multidrug transporters such as P-glycoprotein (P-gp) may play a significant role in pharmacoresistance, by preventing antiepileptic drugs (AEDs) from reaching their targets in the brain. Until now, many studies have described increased P-gp expression in epileptic tissue or have shown that several AEDs act as substrates for P-gp. However, definitive proof showing the functional involvement of P-gp in pharmacoresistance is still lacking. Here we tested whether P-gp contributes to pharmacoresistance to phenytoin (PHT) by using a specific P-gp inhibitor in a model of spontaneous seizures in rats.


METHODS
The effects of PHT on spontaneous seizure activity were investigated in the electrical post-status epilepticus rat model for temporal lobe epilepsy, before and after administration of tariquidar (TQD), a selective inhibitor of P-gp.


RESULTS
A 7-day treatment with therapeutic doses of PHT suppressed spontaneous seizure activity in rats, but only partially. However, an almost complete control of seizures by PHT (93 +/- 7%) was obtained in all rats when PHT was coadministered with TQD. This specific P-gp inhibitor was effective in improving the anticonvulsive action of PHT during the first 3-4 days of the treatment. Western blot analysis confirmed P-gp upregulation in epileptic brains (140-200% of control levels), along with approximately 20% reduced PHT brain levels. Inhibition of P-gp by TQD significantly increased PHT brain levels in chronic epileptic rats.


CONCLUSIONS
These findings show that TQD significantly improves the anticonvulsive action of PHT, thus establishing a proof-of-concept that the administration of AEDs in combination with P-gp inhibitors may be a promising therapeutic strategy in pharmacoresistant patients.
van Vliet
Erwin A
EA
Epilepsy Institute of The Netherlands (SEIN), Heemstede, The Netherlands.
van Schaik
Rosalinde
R
Edelbroek
Peter M
PM
Redeker
Sandra
S
Aronica
Eleonora
E
Wadman
Wytse J
WJ
Marchi
Nicola
N
Vezzani
Annamaria
A
Gorter
Jan A
JA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D004359:Drug Therapy, Combination; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D010672:Phenytoin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014743:Videotape Recording
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D011804:Quinolines; D010672:Phenytoin; C402343:tariquidar