Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.
2012 (English)In: The AAPS journal, ISSN 1550-7416, Vol. 14, no 1, 87-96 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2012. Vol. 14, no 1, 87-96 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-185286DOI: 10.1208/s12248-011-9318-1PubMedID: 22215264OAI: oai:DiVA.org:uu-185286DiVA: diva2:571157