Simple and sensitive liquid chromatographic quantitative analysis of the novel marine anticancer drug Yondelis (ET-743, trabectedin) in human plasma using column switching and tandem mass spectrometric detection.
The development of a simple and sensitive assay for the quantitative analysis of the marine anticancer agent Yondelis (ET-743, trabectedin) in human plasma using liquid chromatography (LC) with column switching and tandem mass spectrometric (MS/MS) detection is described. After protein precipitation with methanol, diluted extracts were injected on to a small LC column (10 x 3.0 mm i.d.) for on-line concentration and further clean-up of the sample. Next, the analyte and deuterated internal standard were back-flushed on to an analytical column for separation and subsequent detection in an API 2000 triple-quadrupole mass spectrometer. The lower limit of quantitation was 0.05 ng mL(-1) using 100 micro l of plasma with a linear dynamic range up to 2.5 ng ml(-1). Validation of the method was performed according to the most recent FDA guidelines for bioanalytical method validation. The time needed for off-line sample preparation has been reduced 10-fold compared with an existing LC/MS/MS method for ET-743 in human plasma, employing a labor-intensive solid-phase extraction procedure for sample pretreatment. The proposed column switching method was successfully applied in phase II clinical trials with Yondelis and pharmacokinetic monitoring.
Stokvis
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Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apess@slz.nl
Rosing
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H
López-Lázaro
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Beijnen
J H
JH
D018906:Antineoplastic Agents, Alkylating / Q000097:blood* / Q000493:pharmacokinetics; D002138:Calibration; D002853:Chromatography, Liquid; D017322:Clinical Trials, Phase II as Topic; D004149:Dioxoles / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D007546:Isoquinolines / Q000097:blood* / Q000493:pharmacokinetics; D013058:Mass Spectrometry / Q000295:instrumentation* / Q000379:methods*; D015394:Molecular Structure; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin