Imaging of P-glycoprotein-mediated pharmacoresistance in the hippocampus: proof-of-concept in a chronic rat model of temporal lobe epilepsy.
OBJECTIVE
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 [(18) F]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 [(18) F]MPPF unidirectional blood-brain clearance (K(1) ; ml/g per min) and the efflux rate constant (k(2) ; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) 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 [(18) F]MPPF k(2) in hippocampus by 27% in nonresponders, without comparable effects in the responder group.


CONCLUSIONS
These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]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.
Bartmann
Hero
H
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
Fuest
Christina
C
la Fougere
Christian
C
Xiong
Guoming
G
Just
Theresa
T
Schlichtiger
Juli
J
Winter
Petra
P
Böning
Guido
G
Wängler
Björn
B
Pekcec
Anton
A
Soerensen
Jonna
J
Bartenstein
Peter
P
Cumming
Paul
P
Potschka
Heidrun
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D010634:Phenobarbital / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000000981:diagnostic imaging / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D011804:Quinolines; C402343:tariquidar; D010634:Phenobarbital