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Epilepsy is a serious neurological disorder that affects more than 60 million people worldwide. Intractable epilepsy (IE) refers to approximately 20%–30% of epileptic patients who fail to achieve seizure control with antiepileptic drug (AED) treatment. Although the mechanisms underlying IE are not well understood, it has been hypothesized that multidrug transporters such as P-glycoprotein (P-gp) play a major role in drug efflux at the blood–brain barrier, and may be the underlying factor in the variable responses of patients to AEDs. The main goal of the present review is to show evidence from different areas that support the idea that the overexpression of P-gp is associated with IE. We discuss here evidence from animal studies, pharmacology, clinical cases and genetic studies. [ABSTRACT FROM PUBLISHER]