Liquid chromatography–tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776

Topoisomerase I (Topo I) is a recognized target for ovarian, lung, and colorectal cancer therapy. The FDA-approved camptothecin (CPT) Topo I inhibitors, topotecan and irinotecan are labile and their effects are rapidly reversible. The indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC...

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Bibliographic Details
Published in:Journal of pharmaceutical and biomedical analysis 2010-09, Vol.52 (5), p.714-720
Main Authors: Holleran, Julianne L., Parise, Robert A., Yellow-Duke, Archibong E., Egorin, Merrill J., Eiseman, Julie L., Covey, Joseph M., Beumer, Jan H.
Format: Article
Language:English
Subjects:
Analysis
Analytical, structural and metabolic biochemistry
Assay
Benzodioxoles - blood
Benzodioxoles - pharmacology
Biological and medical sciences
Calibration
Chromatography, Liquid - methods
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
General pharmacology
Humans
Indenoisoquinolines
Isoquinolines - blood
Isoquinolines - pharmacology
Limit of Detection
Medical sciences
Pharmacology. Drug treatments
Reproducibility of Results
Tandem mass spectrometry
Tandem Mass Spectrometry - methods
Topoisomerase
Topoisomerase I Inhibitors
Validation
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Summary:Topoisomerase I (Topo I) is a recognized target for ovarian, lung, and colorectal cancer therapy. The FDA-approved camptothecin (CPT) Topo I inhibitors, topotecan and irinotecan are labile and their effects are rapidly reversible. The indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776, have been developed as a new generation of Topo I inhibitors and are being advanced to clinical evaluation. To support the clinical development of NSC 743400 and NSC 725776, we developed and validated, according to FDA guidelines, LC–MS/MS assays for the sensitive, accurate and precise quantitation of NSC 743400 and NSC 725776 in 0.2 mL human plasma. After ethyl acetate extraction, separation was achieved with a Synergi Polar RP column and a gradient of 0.1% formic acid in acetonitrile:water. NSC 743400 and NSC 725776 eluted at approximately 3 min, and the total run time was 14 min. Detection consisted of electrospray, positive-mode ionization mass spectrometry. Between 3 and 1000 ng/mL, accuracy was 96.9–108.2% for NSC 743400 and 95.1–106.7% for NSC 725776, and precision was
ISSN:0731-7085
1873-264X
1873-264X
DOI:10.1016/j.jpba.2010.02.020