title: Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions.
abstract: Epilepsy is a common neurological disorder. About one-third of epilepsy patients have a multidrug resistance (MDR) phenotype and develop refractory epilepsy (RE). Changes in the properties of the antiepileptic drugs (AEDs) targets resulting in reduced drug sensitivity, can't explain the MDR phenotype. This particular refractoriness is now attributed to overexpression of multidrug transporters in brain, leading to impaired access of AEDs to CNS targets, and it was documented in both human as well as in experimental models of RE. Single nucleotide polymorphism (SNP) identified in the MDR1-ABCB1 gene (C3435T/CC-genotype) is associated with increased intestinal expression of P-glycoprotein (P-gp) that affects levels of AEDs in plasma. The functional studies of P-gp using P-gp inhibitors could show the still unclear clinical impact of ABCB1 polymorphisms on AEDs resistance. Some drug-drug interactions previously believed to be cytochrome P450 (CYP) mediated are now also considered to be due to the modulation of multidrug-transporters. Because in certain cases pharmacoresistance can be overcome by add-on therapy, co-administered P-gp inhibitors could contribute to the effectiveness of AEDs treatment in RE. And in this regard, perhaps we can postulate to P-gp as a new clinical therapeutic target in multidrug-refractory epilepsy.
authors.affiliation: Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires, Argentina. nadiatom@med.unc.edu
authors.forename: Alberto
authors.initials: A
authors.lastname: Lazarowski
authors.forename: Liliana
authors.initials: L
authors.lastname: Czornyj
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000927:Anticonvulsants / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants