Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations.
Approximately one-third of patients with epilepsy display an inherent resistance to pharmacological therapy, manifest as continuing seizures despite maximal tolerated doses of anti-epileptic drugs. One hypothesis for the underlying mechanism of anti-epileptic drug pharmacoresistance is lower drug entry to the epileptic neurones due to the activity of multidrug efflux pumps from the ATP Binding Cassette (ABC) superfamily at the blood-brain barrier. There has been a steady accumulation of animal and human data supporting this theory, particularly for ABC(B1) (P-glycoprotein). However, much of this evidence is indirect. In the present study, several anti-epileptic drugs (carbamazepine, valproic acid, phenytoin, lamotrigine and primidone) were examined for their ability to interact with three ABC transporters that have been implicated pharmacoresistance of anti-epileptic drugs - ABC(B1), ABC(C1) and ABC(G2). Interaction of anti-epileptic drugs with the transporters was assessed by determining whether they could reverse the ability of multidrug ABC transporters to confer a drug resistance phenotype on cancer cell lines. None of these compounds was able to affect the phenotype, suggesting an absence of any interaction with the multidrug transporters. This finding was further investigated by examination of transporter activity; namely the ability to reduce steady-state intracellular [(3)H]-radiolabelled drug accumulation. None of the anti-epileptic drugs affected labelled drug accumulation by any of the triumvirate of multidrug transporters examined, indicating that they are unlikely to be substrates. The lack of direct modulation by anti-epileptic drugs of ABC transporter function suggests that these proteins do not contribute significantly to resistance in epilepsy.
Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
Francesca
F
Rivers
Terence J
TJ
O'Brien
Richard
R
Callaghan
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000465:Algorithms; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D016014:Linear Models; D010641:Phenotype; D011869:Radioligand Assay
D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D000970:Antineoplastic Agents