Inhibition of the Multidrug Transporter P‐Glycoprotein Improves Seizure Control in Phenytoin‐treated Chronic Epileptic Rats

Abstract

Summary: 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 ∼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.