Mechanisms of drug resistance

Despite the use of new antiepileptic drugs, approximately one third of patients with epilepsy have seizures that cannot be controlled satisfactorily by medical treatment. Drug resistance may exist at the time of the first seizure or may develop later as result of the disease process. The mechanisms of these different scenarios are likely to be multifactorial, and may include alterations in brain uptake or brain targets of antiepileptic drugs. Such alterations may be constitutive (intrinsic), thus underlying de novo drug resistance in epilepsy, or induced, e.g., as a consequence of recurrent seizures or disease progression. Alterations in drug efflux ("multidrug") transporters and drug targets, such as voltage-gated sodium channels, have been found in epileptogenic brain tissue from both patients with epilepsy, and rodent models of epilepsy. However, although the multidrug transporter and target hypotheses are biologically plausible, proof-of-principle is lacking for these hypotheses. An advantage of the multidrug transporter hypothesis is that it can be validated both experimentally and clinically by combining antiepileptic drugs with inhibitors of such transporters. Selective inhibitors of the major efflux transporter P-glycoprotein are currently in clinical trials for reversing chemotherapy resistance in oncology and may soon be used to determine whether such inhibitors can prevent or reverse drug resistance in epilepsy.