Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.
This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood-brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood-brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level.
Division of Pharmacology, LACDR, Leiden University, The Netherlands. s.syvanen@lacdr.leidenuniv.nl
Stina
S
Syvänen
Maarten
M
Schenke
Dirk-Jan
DJ
van den Berg
Rob A
RA
Voskuyl
Elizabeth C
EC
de Lange
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D017551:Microdialysis / Q000379:methods; D017711:Nonlinear Dynamics; D011802:Quinidine / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000503:physiopathology*; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; D011802:Quinidine; C402343:tariquidar; D007608:Kainic Acid