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Gas-chromatographic analysis of busulfan for therapeutic drug monitoring

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Abstract

The development and validation of a gas chromatographic assay method for determination of total and free busulfan concentrations in human plasma for pharmacokinetic studies is reported. 1,6-Bis(methanesulfonyloxy)hexane, the internal standard, and a potential metabolite, 3-hydroxysulfolane, were synthesized. Plasma and plasma ultrafiltrate samples containing busulfan and internal standard were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to gas chromatographic determination. The63Ni electron-capture detector provided a limit of detection of 0.0600 μg/ml with a limit of quantitation of 0.100 μg/ml busulfan in biological samples. Calibration curves were linear from 0.100 to 3.00 μg/ml in plasma (500 μl) and 0.100 to 2.00 μg/ml in plasma ultrafiltrate (100 μl). Extraction and derivatization yields ranged from 78.4% to 89.6% and 56.0% to 71.3%, respectively. Specificity of this assay for busulfan in the presence of its potential metabolites was demonstrated. Also, plasma samples containing co-administered drugs gave no response under these conditions. Clinical samples obtained following administration of a 1 mg/kg oral busulfan dose demonstrate the applicability of this method to analysis of total and free plasma concentrations.

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Authors and Affiliations

  1. Division of Medical Oncology, Section of Laboratory Operations, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, B. C., Canada

    Leanne Embree, Jean R. Heggie, Daria O. Hartley, Norma J. Hudon & James H. Goldie

  2. Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B. C., Canada

    Leanne Embree & Robbin B. Burns

  3. Leukemia and Bone Marrow Transplantation Program of British Columbia, Division of Hematology, British Columbia Cancer Agency, Vancouver General Hospital and Faculty of Medicine, University of British Columbia, Vancouver, B.C., Canada

    Gordon L. Phillips, Donna E. Reece & John J. Spinelli

  4. Division of Medical Oncology, British Columbia Cancer Agency and Faculty of Medicine, University of British Columbia, Vancouver, B. C., Canada

    James H. Goldie

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  1. Leanne Embree
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  2. Robbin B. Burns
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  3. Jean R. Heggie
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  4. Gordon L. Phillips
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  5. Donna E. Reece
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  6. John J. Spinelli
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  7. Daria O. Hartley
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  8. Norma J. Hudon
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Additional information

This work was supported in part by Burroughs Wellcome Inc. and the British Columbia Cancer Agency.

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Embree, L., Burns, R.B., Heggie, J.R. et al. Gas-chromatographic analysis of busulfan for therapeutic drug monitoring. Cancer Chemother. Pharmacol. 32, 137–142 (1993). https://doi.org/10.1007/BF00685617

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