Recent development in high-throughput bioanalytical support for<i>in vitro</i>ADMET profiling

Shou, Wilson Z.; Zhang, Jun

doi:10.1517/17425250903547829

Cited by 37 publications

(10 citation statements)

References 151 publications

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“…[9][10][11][12] However, at a total cycle time of more than 4 min per injection, these methods are not suitable for a high-throughput ADME screening environment whereby thousands of samples are generated and analyzed every day. [13,19] To address this challenge and support a high-throughput in vitro P-gp inhibition screen, we developed an ultrafast bioanalytical method for digoxin with a total cycle time of 9 s per injection, using a RapidFire™ 200 system (BIOCIUS Life Sciences, Woburn, MA, USA) with tandem mass spectrometric detection (RF-MS/MS). [14] Unlike LC-MS/MS, the RapdiFire™ uses an online solid-phase extraction (SPE) system equipped with a fast moving sample aspirator to perform matrix clean-up prior to analysis by atmospheric pressure ionization-tandem mass spectrometry (API-MS/MS).…”

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confidence: 99%

“…An additional advantage that RF-MS/MS enjoys is that it requires either no or very minimal changes in sample preparation as compared to LC-MS/MS analysis, making it easy to be incorporated into existing automated in vitro assays. [19] To date this technology has been successfully used to support several high-throughput screening assays, [20,21] cytochrome P450 (CYP) inhibition assays, [22,23] as well as a metabolic stability assay, [24] and in this manuscript we describe the development of a sensitive, selective, reproducible and robust RF-MS/MS method for digoxin bioanalysis to support an in vitro P-gp inhibition screen.…”

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confidence: 99%

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Ultrafast mass spectrometry based bioanalytical method for digoxin supporting an in vitro P‐glycoprotein (P‐gp) inhibition screen

Wagner

Kolb

Özbal³

et al. 2011

Rapid Comm Mass Spectrometry

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The evaluation of interactions between drug candidates and transporters such as P-glycoprotein (P-gp) has gained considerable interest in drug discovery and development. Inhibition of P-gp can be assessed by performing bi-directional permeability studies with in vitro P-gp-expressing cellular model systems such as Caco-2 (human colon carcinoma) cells, using digoxin as a substrate probe. Existing methodologies include either assaying (3)H-digoxin with liquid scintillation counting (LSC) detection or assaying non-labeled digoxin with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis at a speed of several minutes per sample. However, it is not feasible to achieve a throughput high enough using these approaches to sustain an early liability screen that generates more than a thousand samples on a daily basis. To address this challenge, we developed an ultrafast (9 s per sample) bioanalytical method for digoxin analysis using RapidFire™, an on-line solid-phase extraction (SPE) system, with MS/MS detection. A stable isotope labeled analog, d3-digoxin, was used as internal standard to minimize potential ionization matrix effect during the RF-MS/MS analysis. The RF-MS/MS method was more than 16 times faster than the LC-MS/MS method but demonstrated similar sensitivity, selectivity, reproducibility, linearity and robustness. P-gp inhibition results of multiple validation compounds obtained with this RF-MS/MS method were in agreement with those generated by both the LC-MS/MS method and the (3)H-radiolabel assay. This method has been successfully deployed to assess P-gp inhibition potential as an important early liability screen for drug-transporter interaction.

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confidence: 99%

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confidence: 99%

Ultrafast mass spectrometry based bioanalytical method for digoxin supporting an in vitro P‐glycoprotein (P‐gp) inhibition screen

Wagner

Kolb

Özbal³

et al. 2011

Rapid Comm Mass Spectrometry

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“…High‐throughput analysis, in the field of high‐demand clinical diagnostic testing, but especially in the area of drug discovery and development, is of great importance, and has significant cost implications. As a technique with clear benefits for high‐throughput analyses, TurboFlow and multiplexing technologies are mentioned in a number of reviews (Jemal, ; Hopfgartner and Bourgogne, ; Niessen, ; Berna et al ., ; Herman, ; Souverain et al ., ; Mullett, ; Prakash et al ., ; Xu et al ., ; Carlson and Fisher, ; Nováková and Vlčová, ; Medvedovici et al ., ; Shou and Zhang, ; Schebb et al ., ).…”

Section: Turboflow – Modes Of Operationmentioning

confidence: 97%

Turbulent flow chromatography in bioanalysis: a review

Couchman¹

2012

Biomedical Chromatography

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With advances in fast chromatography techniques, and highly sensitive and selective detection methods such as tandem mass spectrometry, very high-throughput bioanalytical methods can now be easily developed. The bottleneck of the analytical process then becomes the sample preparation, which it is now realized is crucial to the robust operation of the analytical system, especially for quantitative assays. Turbulent flow liquid chromatography was developed in the late 1990s, and combines 'size exclusion' and traditional stationary phase column chemistry to separate macromolecules, such as proteins, from smaller molecules and analytes of interest in biological fluids. By definition, the process is very rapid, and the instrumentation and software have been developed for fully automated, on-line extraction of neat biological fluids. This work aims to review the chromatographic theory of turbulent flow chromatography and illustrate, using examples from recent literature, the application of this technique to a range of analytes from a number of different biological matrices.

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“…Traditionally, the early stages of the drug-discovery process rely on in vitro assays, conventional highthroughput liquid chromatography (LC)-tandem mass spectrometry (MS/MS) (Weigelt, 2009; , 2010;Shou and Zhang, 2010). Although in vitro assays are effective, more and more researchers are adopting cellbased assays to address this early phase of drug development.…”

Section: Transgenic Zebrafish Tumor Models: Bringing New Light To Drumentioning

confidence: 99%

One step forward: The use of transgenic zebrafish tumor model in drug screens

Huang

Nguyễn

et al. 2011

Birth Defects Research Part C: Embryo Today: Reviews

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The zebrafish (Danio rerio) has been an experimental model in the developmental biology and toxicology since the 1950s. In recent years, with the aid of transgenic technology, it has also gained an increasing popularity to model human diseases, including various cancers. As a feasible vertebrate model for large-scale chemical screens, the zebrafish has also given us a new option for the search of potential anticancer drugs. It is hopeful that in the near future with automation and analytical tools, drug development processes will be significantly shortened for quick and effective identification of candidate drugs.

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Recent development in high-throughput bioanalytical support forin vitroADMET profiling

Cited by 37 publications

References 151 publications

Ultrafast mass spectrometry based bioanalytical method for digoxin supporting an in vitro P‐glycoprotein (P‐gp) inhibition screen

Ultrafast mass spectrometry based bioanalytical method for digoxin supporting an in vitro P‐glycoprotein (P‐gp) inhibition screen

Turbulent flow chromatography in bioanalysis: a review

One step forward: The use of transgenic zebrafish tumor model in drug screens

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