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Imaging of P-glycoprotein Function and Expression to Elucidate Mechanisms of Pharmacoresistance in Epilepsy

[ Vol. 10 , Issue. 17 ]

Author(s):

Wolfgang Loscher and Oliver Langer   Pages 1785 - 1791 ( 7 )

Abstract:


The issue of pharmacoresistance in epilepsy has received considerable attention in recent years, and a number of plausible hypotheses have been proposed. Of these, the so-called transporter hypothesis is the most extensively researched and documented. This hypothesis assumes that refractory epilepsy is associated with a localised over-expression of drug transporter proteins such as P-glycoprotein (Pgp) in the region of the epileptic focus, which actively extrudes antiepileptic drugs (AEDs) from their intended site of action. However, although this hypothesis has biological plausibility, there is no clinical evidence to support the assertion that AEDs are sufficiently strong substrates for transportermediated extrusion from the brain. The use of modern brain imaging techniques to determine Pgp function in patients with refractory epilepsy has started only recently, and may ultimately determine whether increased expression and function of Pgp or other efflux transporters are involved in AED resistance.

Keywords:

Multidrug transporters, antiepileptic drugs, brain imaging, positron emission tomography, verapamil, tariquidar, P-glycoprotein, Epilepsy, Antiepileptic drugs (AEDs), Erapamil, blood-brain barrier (BBB), CNS disorder, Temporal lobe epilepsy (TLE), Pgp expression, Single photon emission computed tomography (SPECT), Magnetic resonance spectroscopy (MRS), Radiotracers, Pgp substrates, [11C]daunorubicin, [11C]colchicine, [18F]paclitaxel, [11C]carvedilol, [11C]loperamide, [11C]-Ndesmethyl-loperamide, cyclosporin A (CsA), (R)-enantiomer, (S)-enantiomer, Cytochrome P450-mediated metabolism, Pgp function, liquid chromatography tandem mass spectrometry (LC/MS/MS), Chinese hamster ovary resistant cells (CHrB30), [99mTc]sestamibi, Single nucleotide polymorphism (SNP), [11C]phenobarbital, [11C]phenytoin

Affiliation:

Department of Pharmacology,Toxicology and Pharmacy, University of Veterinary Medicine Hannover, B├╝nteweg 17, D-30559 Hannover, Germany.



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