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Vol. 301, Issue 1, 7-14, April 2002
Department of Pharmacology, Toxicology, and Pharmacy, School of
Veterinary Medicine, Hannover, Germany
Epilepsy, one of the most common neurologic disorders, is a major
public health issue. Despite more than 20 approved antiepileptic drugs
(AEDs), about 30% of patients are refractory to treatment. An
important characteristic of pharmacoresistant epilepsy is that most
patients with refractory epilepsy are resistant to several, if not all,
AEDs, even though these drugs act by different mechanisms. This argues
against epilepsy-induced alterations in specific drug targets as a
major cause of pharmacoresistant epilepsy, but rather points to
nonspecific and possibly adaptive mechanisms, such as decreased drug
uptake into the brain by intrinsic or acquired over-expression of
multidrug transporters in the blood-brain barrier (BBB). There is
accumulating evidence demonstrating that multidrug transporters such as
P-glycoprotein (PGP) and members of the multidrug resistance-associated
protein (MRP) family are over-expressed in capillary endothelial cells
and astrocytes in epileptogenic brain tissue surgically resected from
patients with medically intractable epilepsy. PGP and MRPs in the BBB
are thought to act as an active defense mechanism, restricting the
penetration of lipophilic substances into the brain. A large variety of
compounds, including many lipophilic drugs, are substrates for either
PGP or MRPs or both. It is thus not astonishing that several AEDs, which have been made lipophilic to penetrate into the brain, seem to be
substrates for multidrug transporters in the BBB. Over-expression of
such transporters in epileptogenic tissue is thus likely to reduce the
amount of drug that reaches the epileptic neurons, which would be a
likely explanation for pharmacoresistance. PGP and MRPs can be blocked
by specific inhibitors, which raises the option to use such inhibitors
as adjunctive treatment for medically refractory epilepsy. However,
although over-expression of multidrug transporters is a novel and
reasonable hypothesis to explain multidrug resistance in epilepsy,
further studies are needed to establish this concept. Furthermore,
there are certainly other mechanisms of pharmacoresistance that need to
be identified.
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