Role of multidrug transporters in pharmacoresistance to XXXX .

@entity1 @entity1262 @entity22149 @entity16 @entity302 @entity734 @entity528
@entity302 , one of the most common @entity16 , is a major public health issue. Despite more than 20 approved @entity734 ( @entity734 ), about 30% of @entity1 are refractory to treatment. An important characteristic of pharmacoresistant @entity302 is that most @entity1 with @entity302 are resistant to several, if not all, @entity734 , even though these drugs act by different mechanisms. This argues against @entity302 -induced alterations in specific drug targets as a major cause of pharmacoresistant @entity302 , 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 @entity1262 ( @entity1262 ) and members of the @entity22149 ( @entity22149 ) family are over-expressed in capillary endothelial cells and astrocytes in epileptogenic brain tissue surgically resected from @entity1 with medically intractable @entity302 . @entity1262 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 @entity1262 or MRPs or both. It is thus not astonishing that several @entity734 , 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 @entity528 , which would be a likely explanation for pharmacoresistance. @entity1262 and MRPs can be blocked by specific inhibitors, which raises the option to use such inhibitors as adjunctive treatment for medically @entity302 . However, although over-expression of multidrug transporters is a novel and reasonable hypothesis to explain multidrug resistance in @entity302 , further studies are needed to establish this concept. Furthermore, there are certainly other mechanisms of pharmacoresistance that need to be identified.
