The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy

Abstract

Drug-resistant epilepsy has been explained by different mechanisms. The most accepted one involves overexpression of multidrug transporters proteins at the blood brain barrier and brain metabolizing enzymes. This hypothesis is one of the main pharmacokinetic reasons that lead to the lack of response of some antiseizure drug substrates of these transporters and enzymes due to their limited entrance into the brain and limited stay at the sites of actions. Although uncontrolled seizures can be the cause of the overexpression, some antiseizure medications themselves can cause such overexpression leading to treatment failure and thus refractoriness. However, it has to be taken into account that the inductive effect of some drugs such as carbamazepine or phenytoin not only impacts on the brain but also on the rest of the body with different intensity, influencing the amount of drug available for the central nervous system. Such induction is not only local drug concentration but also time dependent. In the case of valproic acid, the deficient disposition of ammonia due to a malfunction of the urea cycle, which would have its origin in an intrinsic deficiency of L-carnitine levels in the patient or by its depletion caused by the action of this antiseizure drug, could lead to drug-resistant epilepsy. Many efforts have been made to change this situation. In order to name some, the administration of once-daily dosing of phenytoin or the coadministration of carnitine with valproic acid would be preferable to avoid iatrogenic refractoriness. Another could be the use of an adjuvant drug that down-regulates the expression of transporters. In this case, the use of cannabidiol with antiseizure properties itself and able to diminish the overexpression of these transporters in the brain could be a novel therapy in order to allow penetration of other antiseizure medications into the brain.

Keywords: L-carnitine deficiency; efflux transporter overexpression; iatrogenic refractoriness; metabolizing enzyme overexpression; pharmacokinetic hypothesis; therapeutic management.