Mechanisms of antiepileptic drug resistance.
OBJECTIVE
The present review considers new developments in the study and our understanding of resistance to treatment with antiepileptic drugs in epilepsy.


RESULTS
Studies suggest that mechanisms of resistance to drug treatment that operate in other diseases may also be relevant in human and animal drug-resistant epilepsy. Immunohistochemical and molecular genetic data show that there is overexpression of a number of genes and proteins that mediate nonspecific resistance to drug treatment. In particular, there is upregulation of P-glycoprotein and multidrug resistance-associated proteins 1 and 2. These proteins appear to be expressed in cerebral parenchymal cell populations that do not normally do so. Work in animal models suggests that these proteins are able to reduce the local concentration of antiepileptic drugs. Although these proteins are therefore good candidates for mediators of drug resistance, there is still limited proof that they are functionally important in human drug-resistant epilepsy.


CONCLUSIONS
Careful attention needs to be given to the identification and confirmation of the practical importance of mechanisms postulated to underlie drug resistance in human epilepsy. If certain mechanisms are shown to be involved, then new therapeutic options for drug-resistant human epilepsy may be forthcoming.
Sisodiya
Sanjay M
SM
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. sisodiya@ion.ucl.ac.uk
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D027425:ATP-Binding Cassette, Sub-Family C Proteins