MDR1 GENE-EXPRESSION IN BRAIN OF PATIENTS WITH MEDICALLY INTRACTABLE EPILEPSY

Why some patients with seizures are successfully treated with antiepil eptic drugs (AEDs) and others prove medically intractable is not known . Inadequate intraparenchymal drug concentration is a possible mechani sm of resistance to AEDs. The multiple drug resistance gene (MDR1) enc odes P-glycoprotein, an energy-dependent efflux pump that exports plan ar hydrophobic molecules from the cell. If P-glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are expo rted by P-glycoprotein, lower intraparenchymal drug concentrations cou ld contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels >10 times greater than those in normal brain, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Immunohistochemistry for P-glycoprotei n from 14 of the patients showed increased staining in capillary endot helium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRN A levels, expression of P-glycoprotein in astrocytes also was identifi ed. Last, steady-state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1-neg ative cells. MDR1 expression is increased in brain of some patients wi th medically intractable epilepsy, suggesting that the patients' lack of response to medication may be caused by inadequate accumulation of AED in brain.