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Alteration in P-gly...
Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate.
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- Syvänen, Stina (författare)
- Leiden University
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Schenke, Maarten (författare)
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van den Berg, Dirk-Jan (författare)
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Voskuyl, Rob A (författare)
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de Lange, Elizabeth C (författare)
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(creator_code:org_t)
- 2012-01-04
- 2012
- Engelska.
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 14:1, s. 87-96
- Relaterad länk:
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https://link.springe...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
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