Over-expression of Pglycoprotein in malformations of cortical development

Sisodiya, Sanjay M.; Heffernan, Josephine; Squier, M. V.

doi:10.1097/00001756-199911080-00032

Cited by 114 publications

(73 citation statements)

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“…74 However, constitutive rather than induced or acquired overexpression of multidrug transporters has been reported in patients with malformations of cortical development. 66 In addition to intrinsic or acquired overexpression of multidrug transporters in the BBB of patients with epilepsy, functional polymorphisms of these transporters may play a role in pharmacoresistance. 75,76 Furthermore, both overexpression and functional polymorphisms of multidrug transporters in patients with intractable epilepsy need not necessarily be restricted to the brain, but could also occur in other tissues, such as the small intestine, where PGP is thought to form a barrier against entrance of drugs from the interstinal lumen into the bloodstream, thereby limiting their oral bioavailability.…”

Section: Role Of the Bbb Abc Transporters In Drug Resistancementioning

confidence: 99%

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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Section: Role Of the Bbb Abc Transporters In Drug Resistancementioning

confidence: 99%

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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“…Subsequently, it was shown by other groups that, in addition to PGP, MRP1 and MRP2 are over-expressed in the brain tissue of pharmacoresistant patients (Table 1A). Sisodiya et al (1999) reported over-expression of PGP in glial cells of brain samples from patients with malformations of cortical development, which are often associated with medically intractable epilepsy. In a subsequent study, Sisodiya et al (2001) found over-expression of MRP1 in dysplastic neurons, glia, and around vessels in surgically resected epileptogenic human brain tissue of patients with focal cortical dysplasia (FCD), an important malformation of cortical development causing refractory epilepsy.…”

Section: Over-expression Of Multidrug Transporters In Brain Tissue Ofmentioning

confidence: 99%

Role of Multidrug Transporters in Pharmacoresistance to Antiepileptic Drugs

Löscher¹,

Potschka²

2002

J Pharmacol Exp Ther

371

282

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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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“…5 In patients with epilepsy, the multidrug-resistance phenotype is associated with increased lesional ABCB1 levels in resected brain tissue. [6][7][8][9][10][11] Thus, the ABCB1 gene is an important candidate gene potentially influencing the response to antiepileptic drugs. To evaluate its involvement in drug resistance in epilepsy and explore its pharmacogenomics, we typed the ABCB1 polymorphism (C to T) at position 3435 in 315 patients with epilepsy classified as either drug-resistant or drug-responsive.…”

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confidence: 99%