Abstracts

The overexpression of multidrug transporters (MDTs) in the blood-brain barrier (BBB), particularly of P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated proteins (MRPs, ABCC), is discussed to be involved in pharmacoresistance to antiepileptic drugs (AEDs). It has been demonstrated that this overexpression is correlated with seizure severity and duration. This MDT overexpression may hamper a successful treatment of status epilepticus (SE). Our previous studies revealed that the brain access of several AEDs (e.g. phenytoin and phenobarbital) may be limited by MDTs. Other studies indicate that MRPs are involved in the efflux of valproic acid (VPA) at the BBB. However, VPA is known to be often efficacious in treatment of patients with SE resistant to benzodiazepines or phenytoin. As well as for SE as with regard to chronic treatment of epilepsy, the aim of the study presented here was to investigate whether P-gp or in particular MRP2 is involved in VPA transport at the BBB. We performed in vitro transport assays with cell lines overexpressing P-gp or MRP2, respectively, and we performed brain microdialysis experiments in rats applying two strategies to demonstrate MDT function. Verapamil and probenecid were used to inhibit MDTs in normal rats. Furthermore brain access of VPA was compared between mutant rats lacking MRP2 and wildtype rats of the background strain. No significant in vitro transport of VPA nor any significant impact of MDTs on extracellular brain levels in rats could be found. VPA was the first AED we investigated so far passing this variety of tests without any indication of transport by P-gp or MRP2. The lack of P-gp and MRP2 to limit the brain access of VPA would provide an explanation for the efficacy of VPA especially in SE patients that are resistant to other AEDs. Currently, we investigate a potential impact of MDTs on intracellular VPA brain concentration. (Supported by Deutsche Forschungsgemeinschaft (Bonn, Germany) and Desitin Arzneimittel GmbH (Hamburg,Germany).)