Laboratory of Microdialysis

Budapest, Hungary

Laboratory of Microdialysis

Budapest, Hungary

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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.


PubMed | Laboratory of Microdialysis
Type: Journal Article | Journal: Journal of biomolecular screening | Year: 2011

This study provides evidence that quinidine can be used as a probe substrate for ABCB1 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 ABCB1. Effects of quinidine and substrate-inhibitor interactions were tested in a membrane assay and in monolayer assays. The authors compared quinidine and digoxin as ABCB1 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-MDR1 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 ABCB1 at the BBB, resulting in an increased brain penetration of quinidine. In sum, quinidine is a good probe to study ABCB1 function at the BBB. Moreover, quinidine/PSC-833 is an ABCB1-specific substrate/inhibitor combination applicable to many assay systems both in vitro and in vivo.


PubMed | Laboratory of Microdialysis
Type: Journal Article | Journal: Brain research bulletin | Year: 2012

TAK-285, an investigational, orally active HER2/EGRF inhibitor is in clinical development for potential use in HER2 over-expressing metastatic breast cancer. The objective of the present work was to verify the presence of unbound TAK-285 in the rat brain after oral administration by a microdialysis technique with simultaneous sampling of blood and brain. In a pilot microdialysis experiment no detectable amount of TAK-285 was found in the brain dialysate samples after oral administration of the drug (50 mg/kg). A conventional pharmacokinetic study was performed simultaneously with the pilot microdialysis study using the same dosing suspension. TAK-285 was detected in the brain even at the last time point when the samples were taken from the animal at the end-point of the microdialysis experiment. The apparent absence of TAK-285 in blood and brain dialysate samples might be explained by a very low recovery of microdialysis probes for TAK-285 and/or by the adsorption of the compound to the outflow tubing of the microdialysis probes. Results of an in vitro recovery study with TAK-285 were indicative of the strong adsorption of the compound to the microdialysis tubings. Adding bovine serum albumin (4%, w/v) in perfusion fluids and reducing perfusion flow rate (from 1.0 L/min to 0.5 L/min) in in vitro experiments substantially improved the detectability of TAK-285 in dialysate samples. Application of new perfusion conditions resulted in a manifold increase of the relative recovery of the microdialysis set-up for TAK-285 (from 1.6% to 47%). Subsequent in vivo microdialysis experiments were performed using the modified perfusion conditions in animals dosed with TAK-285 (75 mg/kg, p.o.). Detectable level of unbound TAK-285 was found in the extracellular space in the brain as long as 24-28 h after administration of the drug. The brain-to-blood ratios of the unbound TAK-285 were 0.18 and 0.24 (calculated from the C(max) values or from the area under the curve [AUC] values) similarly to the brain-to-blood ratios of total TAK-285. On the basis of substantial brain penetration of unbound TAK-285, it is concluded that TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. The methodological approach described here might help to solve similar problems in determination of brain penetration of other substances with strong adsorption to the tubing of microdialysis setups.

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