title: Gas chromatographic-mass spectrometric quantitation of busulfan in human plasma for therapeutic drug monitoring: a new on-line derivatization procedure for the conversion of busulfan to 1,4-diiodobutane.
abstract: A simplified gas chromatographic-mass spectrometric (GC-MS) analytical method, involving a novel derivatization procedure was developed for monitoring busulfan (Bu) plasma concentrations in populations undergoing bone marrow transplantation. Plasma samples (500 μL) containing Bu-d8 as internal standard were extracted with ethyl acetate (2 mL) followed by centrifugation (1800 rpm, 5 min) and evaporation of the organic layer under nitrogen flow (50 °C). The dry residue was reconstituted with 100 μL iodine solution in acetonitrile (0.25%, w/v) and 3 μL were injected into the GC-MS system at 250 °C. Conversion of Bu to 1,4-diiodobutane was accomplished on-line without the need of an extra derivatization step. MS was operated at selected ion monitoring mode at m/z 183 and 191 corresponding to Bu and Bu-d8 derivatives. Total analysis time was 11.5 min. Calibration curves were linear (mean r=0.9996) over a concentration range of 25-3651 ng/mL using a (1/x)-weighted scheme. Limit of detection and lower limit of quantitation were 10.6 and 25 ng/mL, respectively. Overall accuracy Er (%) was ranging from -5.10% to 10.5%. Within- and between-run RSD (%) were lower 4.51% and 2.15%, respectively. Overall recovery of Bu was equal to 69.3±4.56% (RSD (%)). The present method is sensitive and specific, requiring a simple sample preparation procedure and short analysis time, advantages crucial for therapeutic drug monitoring of Bu in clinical practice and application in pharmacokinetic studies.
authors.affiliation: Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece; Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Athanasiadou
authors.affiliation: Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece. Electronic address: oaka@ath.forthnet.gr.
authors.forename: Yiannis S
authors.initials: YS
authors.lastname: Angelis
authors.affiliation: Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Lyris
authors.affiliation: Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Archontaki
authors.affiliation: Anti Doping Laboratory, P.O. Box 27775 Doha, Qatar.
authors.forename: Costas
authors.initials: C
authors.lastname: Georgakopoulos
authors.affiliation: Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Valsami
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D002066:Busulfan / Q000493:pharmacokinetics*; D002138:Calibration; D016903:Drug Monitoring / Q000379:methods*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D006801:Humans; D006847:Hydrocarbons, Iodinated / Q000032:analysis; D057230:Limit of Detection; D013058:Mass Spectrometry; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006847:Hydrocarbons, Iodinated; C039721:1,4-diiodobutane; D002066:Busulfan
keywords: Busulfan; Gas chromatography; Human plasma; Mass spectrometry; Therapeutic drug monitoring