Abstracts

RATIONALE: Recent reports have shown that multidrug transporters, such as P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRP), are overexpressed in the blood-brain barrier in tissue specimens obtained during epilepsy surgery of patients with drug resistant epilepsy. These findings could explain why pharmacoresistant epileptic patients are resistant to antiepileptic drugs with different mechanisms of anticonvulsant action, provided that multidrug transporters contribute to the regulation of brain levels of such drugs.
METHODS: To determine if multidrug transporters are involved in transport of anticonvulsant drugs to a significant extent, we performed brain microdialysis experiments in freely moving rats. Inhibitors of Pgp (verapamil, PSC833) or of MRP (probenecid) were unilaterally perfused in the frontal cortex, whereas the corresponding vehicle solution was perfused in the contralateral control cortex side. Following i.p. administration of anticonvulsant drugs (phenytoin PHT, carbamazepine CBZ), the influence of inhibitors on extracellular cortical concentrations was determined. Brain-blood ratios were calculated, and values of the inhibitor-treated cortex side were compared with those of the untreated cortex side.
RESULTS: Both verapamil as well as PSC833 significantly elevated PHT cortex levels, as compared to the control cortex side. When the MRP inhibitor probenecid was used for perfusion, cortical PHT concentrations were increased by about two times. In the experiments with CBZ the majority of animals exhibited higher CBZ concentrations at the verapamil treated cortex side as compared to the control cortex side. Preliminary experiments with probenecid also gave evidence for an influence on cortical CBZ levels. In summary the data demonstrate that PHT is transported by both Pgp and MRP to a relevant extent. Data obtained with carbamazepine point to the fact that multidrug transporters are involved in regulation of its extracellular brain levels.
CONCLUSIONS: The present study gave evidence that two major anticonvulsant drugs are substrates of multidrug transporters. Experiments are under way to study if this is also the case for other antiepileptic drugs. If so, overexpression of multidrug transporters in human epilepsy can be considered as a likely explanation of drug resistance in epilepsy, and this would allow novel options for treatment of intractable epilepsy.
Support: DFG LO 274/9-1.