title: Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hammers
authors.affiliation: 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.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.affiliation: 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.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pataraia
authors.affiliation: 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.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Koepp
authors.affiliation: 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.
authors.forename: Aiman
authors.initials: A
authors.lastname: Abrahim
authors.affiliation: 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.
authors.forename: Gert
authors.initials: G
authors.lastname: Luurtsema
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.affiliation: 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.
authors.forename: Raute
authors.initials: R
authors.lastname: Sunder-Plassmann
authors.affiliation: 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.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Zimprich
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Joukhadar
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gentzsch
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Dudczak
authors.affiliation: 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.
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D004351:Drug Resistance; D004828:Epilepsies, Partial / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000706:statistics & numerical data*; D019275:Radiopharmaceuticals; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism; D014018:Tissue Distribution; D014700:Verapamil
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil