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Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP\u2010binding cassette transporters (ABC\u2010t) in different organs, such as the blood\u2010brain barrier (BBB), bowel, liver, and kidney, among others. ABC\u2010t, such as P\u2010glycoprotein (P\u2010gp), multidrug resistance\u2013associated protein (MRP\u20101), and breast cancer\u2013resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The <jats:italic>transporter hypothesis<\/jats:italic> can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC\u2010t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE. These stimuli can induce ABC\u2010t expression in excretory organs and in previously non\u2010expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P\u2010gp indicates that P\u2010gp activity can also produce a significant reduction in resting membrane potential (\u0394\u03a80\u00a0=\u00a0\u221260 to \u221210\u00a0mV). P\u2010gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC\u2010t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.<\/jats:p>","DOI":"10.1002\/epi4.12537","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T14:11:45Z","timestamp":1632147105000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Transporter hypothesis in pharmacoresistant epilepsies. Is\u00a0it at the central or peripheral level?"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7973-8486","authenticated-orcid":false,"given":"Liliana","family":"Czornyj","sequence":"first","affiliation":[{"name":"Neurology Service \u201cJuan P. 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