Abstracts

Rationale: It has been hypothesized that P-glycoprotein (P-gp) is at least partly responsible for drug resistance in epilepsy by hindering anti-epileptic drugs from penetrating the blood-brain barrier and reaching their targets inside the brain^1-2. The objective of this study was to compare the brain distribution of (R)-[¹¹C]verapamil, a frequently used PET tracer for studying P-gp function^3-5, in naïve and epileptic rats and thus to investigate possible differences in P-gp function between these two groups. Methods: Male Sprague-Dawley rats were treated with kainic acid to induce epilepsy (n=20) or with saline (n=20). At 1 week after treatment, each rat underwent a PET study with (R)-[¹¹C]verapamil. In half of the rats of each group, the P-gp inhibitor tariquidar was administered 20-30 minutes prior to the start of the (R)-[¹¹C]verapamil scan. Blood samples were withdrawn during the PET scan and analyzed with regard to tracer metabolism in plasma. Brain radioactivity concentrations, expressed as standardized uptake values (SUV) were compared between naïve and epileptic rats as well as between tariquidar treated and untreated rats. Results: Differences in brain SUV uptake between naïve and epileptic rats were small. In both groups uptake of (R)-[¹¹C]verapamil in the brain was very low with SUV values ranging from 0.60 at the start of the 60 minutes scan to 0.15 at the end of the scan. Pretreatment with tariquidar resulted in an up to 10-fold increase in brain SUV in both naïve and epileptic rats (see fig). In the tariquidar treated rats there was a small tendency towards slower wash-out of verapamil from epileptic rat brains than from naïve rat brains. Plasma kinetics and metabolism of (R)-[¹¹C]verapamil were unaltered by both tariquidar treatment and epilepsy. Conclusions: P-gp function in naïve and epileptic rats appeared to be similar. Therefore, this study did not confirm the hypothesis that P-gp plays a major role in limiting brain uptake of anti-epileptic drugs that are P-gp substrates. P-gp function, however, was investigated 1 week after induction of epilepsy. It cannot be ruled out that P-gp function may be altered significantly at other time points during epileptogenesis following induction of status epilepticus. References: (1) Löscher W et al. (2002) J Pharmacol Exp Ther 301:7-14. (2) Brandt C et al. (2006) Neurobiol Dis 24:202-11. (3) Luurtsema G et al. (2005) Nucl Med Biol 32:87-93. (4) Bankstahl J et al. (2008) J Nucl Med 49:1328-35. (5) Bartels AL et al. (2008) Parkinsonism Relat Disord. 14(6):505-8