Background: Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased\r\ndrug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be\r\nmimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of\r\nspontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in Pglycoprotein\r\n(P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.\r\nMethods: (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET)\r\nligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated\r\nrats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups\r\nwere studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined\r\nusing immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches\r\ncommon in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by\r\npopulation mixed effects modelling (NONMEM).\r\nResults: All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil\r\nbetween saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold\r\nincrease. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate\r\nand saline treated rats.\r\nConclusions: P-gp expression and functionality does not seem to change at early stage after induction of\r\nanticipated pharmacoresistant epilepsy by kainate.
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