Imaging of P‐glycoprotein–mediated pharmacoresistance in the hippocampus: Proof‐of‐concept in a chronic rat model of temporal lobe epilepsy

• Published in: Epilepsia (Copenhagen) 2010-09, Vol.51 (9), p.1780-1790
• Main Authors: Bartmann, Hero, Fuest, Christina, La Fougere, Christian, Xiong, Guoming, Just, Theresa, Schlichtiger, Juli, Winter, Petra, Böning, Guido, Wängler, Björn, Pekcec, Anton, Soerensen, Jonna, Bartenstein, Peter, Cumming, Paul, Potschka, Heidrun
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - metabolism; Brain; Brain - diagnostic imaging; Brain - metabolism; Brain mapping; Carbon Radioisotopes; Disease Models, Animal; Drug resistance; Drug Resistance, Multiple - physiology; Drug‐refractoriness; Epilepsy; Epilepsy, Temporal Lobe - diagnostic imaging; Epilepsy, Temporal Lobe - drug therapy; Epilepsy, Temporal Lobe - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus; Hippocampus - diagnostic imaging; Hippocampus - metabolism; Humans; Kinetics; Medical sciences; Multidrug transporter; Nervous system (semeiology, syndromes); Neuroimaging; Neurology; Neuropharmacology; P-Glycoprotein; Pharmacology. Drug treatments; Pharmacoresistance; Phenobarbital; Phenobarbital - metabolism; Phenobarbital - pharmacology; Phenobarbital - therapeutic use; Positron emission tomography; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Seizures; Seizures - diagnostic imaging; Seizures - metabolism; Temporal lobe; Therapeutic applications; Translation
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2010.02671.x

Summary Purpose:  Based on experimental findings, overexpression of P‐glycoprotein at the blood–brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P‐glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. Methods:  We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P‐glycoprotein substrate [18F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P‐glycoprotein expression than do phenobarbital responders. Results:  Mean baseline parametric maps of the [18F]MPPF unidirectional blood–brain clearance (K1; ml/g per min) and the efflux rate constant (k2; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [18F]MPPF K1 in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [18F]MPPF k2 in hippocampus by 27% in nonresponders, without comparable effects in the responder group. Discussion:  These results constitute a proof‐of‐concept for a novel imaging approach to evaluate blood–brain barrier P‐glycoprotein function in animals. By extension, [18F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P‐glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P‐glycoprotein expression.