Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil.
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.
Langer
Oliver
O
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.
Bauer
Martin
M
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.
Hammers
Alexander
A
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.
Karch
Rudolf
R
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.
Pataraia
Ekaterina
E
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.
Koepp
Matthias J
MJ
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.
Abrahim
Aiman
A
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.
Luurtsema
Gert
G
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.
Brunner
Martin
M
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.
Sunder-Plassmann
Raute
R
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.
Zimprich
Friedrich
F
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.
Joukhadar
Christian
C
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.
Gentzsch
Stephan
S
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.
Dudczak
Robert
R
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.
Kletter
Kurt
K
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.
Müller
Markus
M
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.
Baumgartner
Christoph
C
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.
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil