The causes and mechanisms underlying multidrug resistance (MDR) in
epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic
seizures or
anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability
glycoprotein (P-gp) involved in MDR to various
cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect
anticonvulsant drug concentrations in the brain. Mdr
mRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3-24 hr after
kainic acid-induced limbic
seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of
phenytoin or
carbamazepine for 7 d did not change mdr
mRNA expression in the mouse hippocampus 1-72 hr after the last drug administration. Six hours after
seizures, the brain/plasma ratio of
phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b -/-) lacking P-gp
protein showed a 46% increase in
phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr.
Carbamazepine concentrations were measurable in the hippocampus at 3 hr in mdr1a/b -/- mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous
seizures 3 months after electrically induced
status epilepticus, mdr1
mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp
mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect
antiepileptic drugs concentrations in the brain, suggesting that seizure-induced mdr
mRNA expression contributes to MDR in
epilepsy.