Quinidine as an ABCB1 Probe for Testing Drug Interactions at the Blood–Brain Barrier: An In Vitro In Vivo Correlation Study

Sziráki, István; Erdő, Franciska; Beéry, Erzsébet; Molnár, Petra Magdolna; Fazakas, Csilla; Wilhelm, Imola; Makai, Ildikó; Kis, Emese; Herédi-Szabó, Krisztina; Abonyi, Tibor; Krizbai, István A.; Tóth, Gábor; Krajcsi, Péter

doi:10.1177/1087057111414896

Cited by 28 publications

(36 citation statements)

References 26 publications

(38 reference statements)

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“…This value was ~0.3 for the controls and ~1.0 for the PSC-833-pretreated rats. 11 In the present study in anesthetized control mice, the brain-to-blood ratios were much lower than in rats. The AUC brain to AUC blood ratio was significantly increased (from 0.04-0.17) in the PSC-833-treated mice at the lower QND dose (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…Previously, we have reported 11 that the dual-probe microdialysis approach is an effective tool to assess investigational drugs for P-gp interaction at the BBB in rats. Moreover, we provided evidence that QND-PSC-833 is a P-gp-specific probe substrate/reference inhibitor combination applicable in several assay systems in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In dual-and tripleprobe rat microdialysis experiments, systemically or locally administered PSC-833 increased the brain penetration of QND, suggesting that the microdialysis techniques can be used for in vivo assessment of drugs for P-gp interactions of drugs at the BBB. 11 The Food and Drug Administration recommends digoxin as a P-gp probe substrate in vitro 12 ; however, its in vivo application in preclinical studies is limited because of its low LD 50 value in rodents. 13 In the ATPase assay, QND was superior compared with digoxin (IC 50 values were 7.8 and 68.5 µM, respectively), and in MDCKII and rat brain endothelial cell (RBEC) monolayers, QND also outperformed digoxin.…”

Section: The Use Of Microdialysis Techniques In Mice To Study P-gp Fumentioning

confidence: 99%

“…13 In the ATPase assay, QND was superior compared with digoxin (IC 50 values were 7.8 and 68.5 µM, respectively), and in MDCKII and rat brain endothelial cell (RBEC) monolayers, QND also outperformed digoxin. 11 In vivo microdialysis is a gold-standard technique for determination of unbound, pharmacologically active drug levels in the target tissue. This technique, which involves the surgical implantation of a microdialysis probe into brain or peripheral tissues, is technically very demanding but has many advantages.…”

Section: The Use Of Microdialysis Techniques In Mice To Study P-gp Fumentioning

confidence: 99%

“…9 P-gp mediates the efflux of QND across the BBB, as demonstrated by Kusuhara et al, 10 using the MDR1 inhibitor (PSC-833) and mdr1a knockout mice. In our previous study, 11 an in vitro-in vivo assay system with…”

Section: Introductionmentioning

confidence: 99%

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The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

et al. 2013

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An integrated assay system involving dual/triple-probe microdialysis techniques in rats was developed earlier for testing interactions with P-glycoprotein (P-gp) at the blood-brain barrier using quinidine/PSC-833 as a P-gp substrate/inhibitor combination. The aim of the present study was to expand our assay system to mice using microdialysis with simultaneous sampling of blood and brain and to compare the result with a primary mouse brain endothelial cell monolayer (pMBMEC) assay. Brain penetration of quinidine was dose dependent in both anesthetized and awake mice after intraperitoneal drug administration. PSC-833 pretreatment caused a 2.5-to 3.4-fold increase in quinidine levels of brain dialysate samples in anesthetized or awake animals, after single or repeated administration of PSC-833. In pMBMEC, a 2.0-to 2.5-fold efflux ratio was observed in the transcellular transport of quinidine. The P-gp-mediated vectorial transport of quinidine was eliminated by PSC-833. These results indicate that quinidine with PSC-833 is a good probe substrate-reference inhibitor combination for testing drug-drug interactions with P-gp in the in vivo and in vitro mouse systems. With increasing number of humanized transgenic mice, a test system with mouse microdialysis experimentation becomes more important to predict drug-drug interactions in humans.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: The Use Of Microdialysis Techniques In Mice To Study P-gp Fumentioning

confidence: 99%

Section: The Use Of Microdialysis Techniques In Mice To Study P-gp Fumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

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Pre‐Plated Cell Lines for ADMETox Applications in the Pharmaceutical Industry

Torres¹,

Sáfár

Vázquez‐Sánchez

et al. 2015

CP Toxicology

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Membrane transporters significantly modulate membrane permeability of endobiotics and xenobiotics, such as bile acids and drugs, respectively. Various in vitro methods have been established for both ATP-binding cassette (ABC) transporters to examine cellular efflux and uptake, and for solute carriers (SLC) to examine cellular uptake of substrates. Cell-based systems are the models of choice to test drug-transporter interactions as well as drug-drug interactions for research and regulatory purposes, albeit, for low passive permeability substrates of ABC transporters, vesicular uptake assays are also recommended. Commercially available pre-plated cells (e.g., immortalized or transfected) offer a useful alternative to in-house cell culture. Three main methods are known to manufacture pre-plated cultures: regular culture medium with vacuum seal, cryopreserved delivery, and the solid shipping media technology. The regular culture medium and the solid shipping media technologies provide ready-to-use models for end users. Models expressing a broad selection of transporters are available in pre-plated formats for absorption, distribution, metabolism, excretion, and toxicity (ADMETox) studies. Conversely, the application and utility of pre-plated cultures coupled with personal experiences have not been extensively covered in published research papers or reviews, despite availability and significant use of pre-plated products in the pharmaceutical industry. In this overview, we will briefly describe: 1) in vitro tools commonly used for ADMETox testing; 2) methods employed in manufacturing, shipment and preparation of pre-plated cell lines; 3) cell-membrane barrier models currently available in pre-plated format to reproduce passage restriction of physiological barriers to certain compounds; and 4) recommended pre-plated cell lines overexpressing uptake transporters for ADMETox applications.

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Membrane Assays to Characterize Interaction of Drugs with ABCB1

et al. 2015

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ATP-binding cassette sub-family B member 1 (ABCB1) [P-glycoprotein (P-gp), multidrug resistance protein 1 (MDR1)] can affect the pharmacokinetics, safety, and efficacy of drugs making it important to identify compounds that interact with ABCB1. The ATPase assay and vesicular transport (VT) assay are membrane based assays that can be used to measure the interaction of compounds with ABCB1 at a lower cost and higher throughput compared to cellular-based assays and therefore can be used earlier in the drug development process. To that end, we tested compounds previously identified as ABCB1 substrates and inhibitors for interaction with ABCB1 using the ATPase and VT assays. All compounds tested interacted with ABCB1 in both the ATPase and VT assays. All compounds previously identified as ABCB1 substrates activated ABCB1-mediated ATPase activity in the ATPase assay. All compounds previously identified as ABCB1 inhibitors inhibited the ABCB1-mediated transport in the VT assay. Interestingly, six of the ten compounds previously identified as ABCB1 inhibitors activated the basal ATPase activity in activation assays suggesting that the compounds are substrates of ABCB1 but can inhibit ABCB1 in inhibition assays. Importantly, for ATPase activators the EC50 of activation correlated with the IC50 values from the VT assay showing that interactions of compounds with ABCB1 can be measured with similar levels of potency in either assay. For ATPase nonactivators the IC50 values from the ATPase inhibition and VT inhibition assay showed correlation. These results demonstrate the utility of membrane assays as tools to detect and rank order drug-transporter interactions.

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Quinidine as an ABCB1 Probe for Testing Drug Interactions at the Blood–Brain Barrier: An In Vitro In Vivo Correlation Study

Cited by 28 publications

References 26 publications

The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

The Use of Microdialysis Techniques in Mice to Study P-gp Function at the Blood-Brain Barrier

Pre‐Plated Cell Lines for ADMETox Applications in the Pharmaceutical Industry

Membrane Assays to Characterize Interaction of Drugs with ABCB1

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