Sziraki I.,Laboratory of Microdialysis |
Erdo F.,Laboratory of Microdialysis |
Beery E.,Laboratory of Microdialysis |
Molnar P.M.,University of Szeged |
And 9 more authors.
Journal of Biomolecular Screening | Year: 2011
This study provides evidence that quinidine can be used as a probe substrate for ABCBl in multiple experimental systems both in vitro and in vivo relevant to the blood-brain barrier (BBB). The combination of quinidine and PSC-833 (valspodar) is an effective tool to assess investigational drugs for interactions on ABCBl. Effects of quinidine and substrate-inhibitor interactions were tested in a membrane assay and in monolayer assays. The authors compared quinidine and digoxin as ABCBl probes in the in vitro assays and found that quinidine was more potent and at least as specific as digoxin in ATPase and monolayer efflux assays employing MDCKII-MDRl and the rat brain microcapillary endothelial cell system. Brain exposure to quinidine was tested in dual-/triple-probe microdialysis experiments in rats by assessing levels of quinidine in blood and brain. Comparing quinidine levels in dialysate samples from valspodar-treated and control animals, it is evident that systemic/local administration of the inhibitor diminishes the pumping function of ABCBl at the BBB, resulting in an increased brain penetration of quinidine. In sum, quinidine is a good probe to study ABCBl function at the BBB. Moreover, quinidine/PSC-833 is an ABCB l-specific substrate/inhibitor combination applicable to many assay systems both in vitro and in vivo. © 2011 Society for Laboratory Automation and Screening. Source