Transporter Hypothesis in Pharmacoresistant Epilepsies: Is it at the Central or Peripheral Level?

Abstract

The multidrug resistance (MDR) phenotype characterizes patients withrefractory epilepsy (RE). Seizures are not controlled despite receiving various combinations of more than two anti-seizure drugs (ASMs). The continued design of newASMs did not change the constant percentage (30–40%) of epileptic patients whowill develop the MDR phenotype. Drugs ASMs biodistribution, including theirmetabolites, depends on the functional expression of several transporters of theABC transporters (ABC-t), P-glycoprotein (P-gp), the protein associated with resistance to multidrug (MRP-1) and breast cancer-resistant protein (BCRP). Thesetransporters are constitutively expressed intestine, liver, kidney, and blood-brainbarrier, playing a central role in pharmacokinetic balances. ABC transporters can beinduced by stressful stimuli such as hypoxia, infammation, the drugs administered,and even seizures themselves. Consequently, uncontrolled seizures increase the riskof RE by inducing greater functional expression of these transporters. Based onclinical and experimental fndings, the so-called “transporters hypothesis” arises,which explains the MDR phenotype in ER, even when ASMs are administeredsimultaneously. These stimuli induce the ABC-t expression in cells that normally donot express them, such as neurons and cardiomyocytes, producing membrane depolarization that favors epileptogenesis, and heart failure, respectively, increasing therisk of developing sudden unexpected death in epilepsy (SUDEP).