Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats.

Abstract

PURPOSE:

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.

• Authors: Erwin A van Vliet, Rosalinde van Schaik, Peter M Edelbroek, Sandra Redeker, Eleonora Aronica, Wytse J Wadman, Nicola Marchi, Annamaria Vezzani, Jan A Gorter
• Journal: Epilepsia (Epilepsia) Vol. 47 Issue 4 Pg. 672-80 (Apr 2006) ISSN: 0013-9580 [Print] United States
• PMID: 16650133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anticonvulsants
• Quinolines
• Phenytoin
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism, physiology)
• Animals
• Anticonvulsants (metabolism, pharmacology, therapeutic use)
• Blood-Brain Barrier (drug effects, metabolism)
• Blotting, Western
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Drug Resistance, Multiple (drug effects, physiology)
• Drug Therapy, Combination
• Electrodes, Implanted
• Electroencephalography (drug effects)
• Epilepsy, Temporal Lobe (drug therapy, metabolism, prevention & control)
• Male
• Phenytoin (metabolism, pharmacology, therapeutic use)
• Quinolines (metabolism, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Up-Regulation
• Videotape Recording