Langer Oliver, Bauer Martin, Hammers Alexander, Karch Rudolf, Pataraia Ekaterina, Koepp Matthias J, Abrahim Aiman, Luurtsema Gert, Brunner Martin, Sunder-Plassmann Raute, Zimprich Friedrich, Joukhadar Christian, Gentzsch Stephan, Dudczak Robert, Kletter Kurt, Müller Markus, Baumgartner Christoph
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, AustriaDepartment of Radiopharmaceuticals, Austrian Research Centers GmbH - ARC, Seibersdorf, AustriaDivision of Neuroscience, Faculty of Medicine, Imperial College, and MRC Clinical Sciences Centre, Hammersmith Hospital, London, UKDepartment of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, United KingdomDepartment of Medical Computer Sciences, Medical University of Vienna, Vienna, AustriaDepartment of Neurology, Medical University of Vienna, Vienna, AustriaDepartment of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, The NetherlandsInstitute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, AustriaDepartment of Radiology, Division of Neuroradiology, Medical University of Vienna, Vienna, AustriaDepartment of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
Epilepsia. 2007 Sep;48(9):1774-1784. doi: 10.1111/j.1528-1167.2007.01116.x. Epub 2007 May 1.
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.
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).
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.
癫痫脑组织中多药转运蛋白P-糖蛋白（P-gp）的区域过表达可能会降低抗癫痫药物的靶点部位浓度，从而导致癫痫耐药。我们使用P-gp底物R-[(11)C]维拉帕米和正电子发射断层扫描（PET）来检测耐药性单侧颞叶癫痫患者（n = 7）致痫脑区和非致痫脑区之间P-gp活性的差异。我们比较了位于癫痫灶同侧和对侧的同源脑感兴趣区（VOIs）中R-[(11)C]维拉帕米的动力学。
在不同VOIs中，脉络丛中的放射性最高。海马VOI不能用于数据分析，因为它被来自相邻脉络丛的放射性溢出所污染。在已知参与癫痫发作产生和传播的其他几个颞叶区域中，与对侧相比，R-[(11)C]维拉帕米的同侧流入速率常数K(1)和流出速率常数k(2)在描述上有所增加。参数不对称在海马旁回和环回中最为显著（K(1)，范围：-3.8%至+22.3%；k(2)，范围：-2.3%至+43.9%），杏仁核（K(1)，范围：-20.6%至+31.3%；k(2)，范围：-18.0%至+38.9%），颞叶内侧前部（K(1)，范围：-8.3%至+14.5%；k(2)，范围：-14.5%至+31.0%）和颞叶外侧前部（K(1)，范围：-20.7%至+16.8%；k(2)，范围：-24.4%至+
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