%0 Journal Article
%T (R)-[11C]Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus
%A Stina Syv£¿nen
%A Gert Luurtsema
%A Carla FM Molthoff
%A Albert D Windhorst
%A Marc C Huisman
%A Adriaan A Lammertsma
%A Rob A Voskuyl
%A Elizabeth C de Lange
%J BMC Medical Imaging
%D 2011
%I BioMed Central
%R 10.1186/1471-2342-11-1
%X (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.About 30-40% of all people with epilepsy do not become fully seizure free with present medication, even when treated at the maximal tolerated dose. This pharmacoresistance is particularly prominent in partial epilepsies and some severe syndromes in infants, but essentially it can occur in nearly all types of epilepsies and epileptic syndromes. In addition, unresponsiveness in these patients is not limited to a specific drug or drug class, but occurs with the complete range of antiepileptic drugs (AEDs) [1,2].For a drug to exert its effect, it has to be distributed to its target at a therapeutic concentration and must be able to interact with the target. Several different mechanisms influence transport across the blood-brain barrier (BBB); i.e. passive diffusion, as well as active
%U http://www.biomedcentral.com/1471-2342/11/1