P-glycoprotein and multidrug resistance-associated protein are involved inthe regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain

Despite considerable advances in the pharmacotherapy of epilepsy, about 30% of epileptic patients are refractory to antiepileptic drugs (AEDs). In mos t cases, a patient who is resistant to one major AED is also refractory to other AEDs, although these drugs act by different mechanisms. The mechanism s that lead to drug resistance in epilepsy are not known. Recently, over-ex pression of multidrug transporters, such as P-glycoprotein (PGP) and multid rug resistance-associated protein (MRP), has been reported in surgically re sected epileptogenic human brain tissue and suggested to contribute to the- drug resistance of epilepsy. However, it is not known to what extent multid rug transporters such as PGP or MRP are involved in transport of AEDs. In t he present study, we used in vivo microdialysis in rats to study whether th e concentration of carbamazepine in the extracellular fluid of the cerebral cortex can be enhanced by inhibition of PGP or MRP, using the PGP inhibito r verapamil and the MRP inhibitor probenecid. Local perfusion with verapami l or probenecid via the microdialysis probe increased the extracellular con centration of carbamazepine. The data indicate that both PGP and MRP partic ipate in. the regulation of extracellular brain concentrations of the major AED carbamazepine. (C) 2001 Lippincott Williams & Wilkins.