Summary: Purpose and Methods: Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[11 C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[11 C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus. Results: Among different VOIs, radioactivity was highest in the choroid plexus. The hippocampal VOI could not be used for data analysis because it was contaminated by spill-in of radioactivity from the adjacent choroid plexus. In several other temporal lobe regions that are known to be involved in seizure generation and propagation ipsilateral influx rate constants K 1 and efflux rate constants k 2 of R-[11 C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus (K 1 , range: −3.8% to +22.3%; k 2 , range: −2.3% to +43.9%), amygdala (K 1 , range: −20.6% to +31.3%; k 2 , range: −18.0% to +38.9%), medial anterior temporal lobe (K 1 , range: −8.3% to +14.5%; k 2 , range: −14.5% to +31.0%) and lateral anterior temporal lobe (K 1 , range: −20.7% to +16.8%; k 2 , range: −24.4% to +22.6%). In contrast to temporal lobe VOIs, asymmetries were minimal in a region presumably not involved in epileptogenesis located outside the temporal lobe (superior parietal gyrus, K 1 , range: −3.7% to +4.5%; k 2 , range: −4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux (k 2 ) increases were more pronounced than ipsilateral influx (K 1 ) increases, which resulted in ipsilateral reductions (10%-26%) of R-[11 C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K 1 , k 2 and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p > 0.05, Wilcoxon matched pairs test). Conclusions: Even though we failed to detect statistically significant differences in R-[11 C]verapamil model parameters between epileptogenic and nonepileptogenic brain regions, it cannot be excluded from our pilot data in a small sample size of patients that regionally enhanced P-gp activity might contribute to drug resistance in some patients with temporal lobe epilepsy.

The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood-brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-11 Cverapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB. Methods: A group of 7 Wistar Unilever rats underwent paired (R)-11 C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n 5 5) or vehicle (n 5 2). Results: After tariquidar administration, the distribution volume (DV) of (R)-11 C-verapamil was 12-fold higher than baseline (3.68 6 0.81 vs. 0.30 6 0.08; P 5 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K 1 ) of (R)-11 C-verapamil into the brain, which was about 8-fold higher after tariquidar. A doseresponse assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 6 9.5 mg/kg. Conclusion: Our data demonstrate that (R)-11 C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.

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Increased VPM DV values in the brains of elderly subjects suggest a decrease in cerebral P-gp function with increasing age.