Abstract
BackgroundIncreased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.Methods(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).ResultsAll 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.ConclusionsP-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.
Highlights
Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy
P-glycoprotein (P-gp) is one of the most important efflux transporters of exogenous substances at the blood-brain barrier (BBB) [3,4]. Both clinical and pre-clinical, have indicated that potential changes in Pglycoprotein (P-gp) functionality at the BBB may contribute to decreased target site antiepileptic drugs (AEDs) concentrations in the brain [5,6,7,8,9,10,11,12,13,14,15]
Due to the design of this study it was not possible to determine whether these animals eventually would have developed spontaneous epilepsy, but the signs and symptoms during and after status epilepticus (SE) were very similar to those observed in previous studies where animals did develop epilepsy
Summary
Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. Results: 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. P-glycoprotein (P-gp) is one of the most important efflux transporters of exogenous substances at the BBB [3,4] Several studies, both clinical and pre-clinical, have indicated that P-gp functionality at the BBB may contribute to decreased target site AED concentrations in the brain [5,6,7,8,9,10,11,12,13,14,15]
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