Means, motive, and opportunity: establishing culpability in pharmacoresistant epilepsy

Sills, G. J. (2007) Means, motive, and opportunity: establishing culpability in pharmacoresistant epilepsy. Epilepsy Currents, 7(2), pp. 51-53. (doi: 10.1111/j.1535-7511.2007.00166.x) (PMID:17505553) (PMCID:PMC1867085)

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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% μ 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Sills, G. J.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Epilepsy Currents
ISSN (Online):1535-7511

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