Abstract
Although drug-resistant epilepsy has been explained by different mechanisms, the most accepted one involves overexpression of efflux transporters at the blood-brain barrier and at drug-elimination tissues. Tissue expression of efflux transporters can not only be triggered by some antiseizure medications (ASMs) with inducing properties but also by physiological factors such as redistribution of cardiac output. Tissues with high metabolic rates in need of oxygen and glucose will receive a higher fraction of blood and, thus, any other solutes from blood including ASMs. The increased expression of efflux transporters in these tissues due to the increased cardiac output fractions triggered by the energetic tissue requirements will precisely avoid the entrance of any unnecessary substance. Increased expression and function of transporters in the brain are observed in rest periods when there is a significant withdrawal of blood flow from the skeletal muscles and a persistent influx of magnesium. Then, circadian rest-activity rhythms condition not only the expression of transporters but also their functioning.
Even though glucose is the common fuel for the brain, ketone bodies are a much better source of energy. Apart from the ketogenic diets, ketone bodies can be obtained through physical exercise and through the metabolism of long-chain fatty acids via L-carnitine. Besides, physical activity also decreases the cerebral fraction of cardiac output, contributing then to avoiding its high rate of efflux.
Therefore, possible strategies to overcome drug resistance consist of: administering old ASMs under a bitherapy regime, as is the case of valproate and phenytoin (or another drug of choice) but with different dosing intervals; co-administration of l-carnitine, as a supplement to support an adequate metabolism of fatty acids and also to protect the patient from eventual hyperammonemia valproate can cause; and appropriate routine of physical exercise.
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Fagiolino, P., Vázquez, M. (2023). Contribution of the Antiepileptic Drug Administration Regime to Avoid the Development and/or Establishment of Pharmacoresistant Epilepsy. In: Rocha, L.L., Lazarowski, A., Cavalheiro, E.A. (eds) Pharmacoresistance in Epilepsy. Springer, Cham. https://doi.org/10.1007/978-3-031-36526-3_9
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