Transportadores ABC y resistencia a fármacos en la epilepsia: plausibilidad biológica, farmacogenética y medicina de precisión / ABC transporters and drug resistance in epilepsy: biological plausibility, pharmacogenetics and precision medicine

Introducción: Un mecanismo plausible que puede contribuir a la resistencia a fármacos en la epilepsia es la falta de llegada de los fármacos al tejido encefálico, causado por cambios en la actividad de los transportadores ABC. El principal argumento a favor de esta hipótesis es que la resistencia ocurre frente a una gran variedad de fármacos antiepilépticos con distintos mecanismos de acción, lo que sugiere un fenómeno subyacente no específico que limita la efectividad de los tratamientos farmacológicos. Desarrollo: Se realiza una revisión bibliográfica de los transportadores ABC, su papel en la fisiología normal de la barrera hematoencefálica y en la resistencia a fármacos en la epilepsia, tanto en estudios en humanos como en modelos animales. Se revisan además los estudios de variantes genéticas en los genes ABCB1 y ABCC2, que codifican para estos transportadores, y los recientes estudios genómicos en la epilepsia y patologías afines, discutiendo sus alcances y limitaciones. Conclusiones: Hasta ahora, la asociación de variantes genéticas de transportadores ABC con la resistencia a fármacos anticonvulsionantes sigue siendo materia de debate. Se espera que la creciente masificación y accesibilidad a tecnologías de secuenciación modernas permitan establecer marcadores genéticos que otorguen una aproximación de medicina de precisión para el tratamiento de la epilepsia

Introduction: A plausible mechanism that may contribute to drug resistance in epilepsy is the failure of drugs to reach the brain tissue, caused by changes in the activity of ABC transporters. The main argument in favour of this hypothesis is that resistance occurs against a wide variety of antiepileptic drugs with different mechanisms of action, suggesting a non-specific underlying phenomenon that limits the effectiveness of drug treatments. Development: A review of the literature on ABC transporters, their role in the normal physiology of the blood-brain barrier and drug resistance in epilepsy, both in human studies and in animal models, is conducted. Studies of genetic variants in the ABCB1 and ABCC2 genes, which code for these transporters, and recent genomic studies in epilepsy and related pathologies are also reviewed, followed by a discussion of their scope and limitations. Conclusions: To date, the association of genetic variants of ABC transporters with resistance to anticonvulsant drugs remains a matter of debate. The increasingly widespread use and accessibility of modern sequencing technologies is expected to allow the establishment of genetic markers that provide a precision medicine based approach to the treatment of epilepsy

Lack of Association between the IL6R Gene Asp358Ala Variant (rs2228145), IL-6 Plasma Levels, and Treatment Resistance in Chilean Schizophrenic Patients Treated with Clozapine.

Alterations in neuroinflammatory processes have been suggested to contribute to the development of Schizophrenia (SZ); one component of the inflammatory system that has been linked to this disorder is interleukin-6 (IL-6). The minor allele of rs2228145, a functional polymorphism in the IL-6 receptor gene, has been associated to elevated IL-6 plasma levels and increased inflammatory activity, making it an interesting candidate to study as a possible factor underlying clinical heterogeneity in SZ. We studied a sample of 100 patients undergoing treatment with clozapine. Their symptoms were quantified by Brief Psychotic Rating Scale; those with the lowest scores ("remitted") were compared with the highest ("clozapine treatment resistant"). We determined allelic frequencies for rs2228145 and IL-6 plasma levels. Our results do not support a role of IL-6 in response to treatment with clozapine. Further studies accounting for potential confounding factors are necessary.