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Perspective

P-Glycoprotein—a Clinical Target in Drug-Refractory Epilepsy?

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (R.W.R., S.E.B.); and Clinical Biochemistry Department, School of Pharmacy and Biochemistry (A.L.) and E. de Robertis Neuroscience Research Institute (A.L.), University of Buenos Aires, Argentina

ATP-binding cassette transporters such as P-glycoprotein (Pgp), multidrug resistance-associated protein, and breast cancer resistance protein are known to transport a wide range of substrates and are highly expressed in the capillary endothelial cells that form part of the blood-brain barrier. It is noteworthy that P-glycoprotein has been shown to be up-regulated in animal models of refractory epilepsy, and adding a Pgp inhibitor to treatment regimens has been shown to reverse the drug-resistant phenotype. Limited data have suggested a role for Pgp in epilepsy in humans as well. However, few epilepsy drugs have been shown to be transported by Pgp, leading to controversy over whether Pgp actually plays a role in drug-resistant epilepsy. In this issue of Molecular Pharmacology, Bauer et al. (p. 1444) demonstrate that glutamate can cause localized up-regulation of Pgp via cyclooxygenase-2 (COX-2) and that this phenomenon can be prevented with COX-2 inhibitors. Localized rather than global up-regulation of Pgp may explain some of the difficulty investigators have had in proving a role for Pgp in epilepsy. The results add new support for future clinical trials targeting Pgp expression in drug-refractory epilepsy.

Address correspondence to: Robert W. Robey, 9000 Rockville Pike, Bldg 10 Rm 12C217, Bethesda, MD 20892. robeyr{at}mail.nih.gov

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Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

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