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    Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.

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    Authors
    Bronchud, Miguel H
    Margison, Jennifer M
    Howell, Anthony
    Lind, Michael J
    Lucas, S B
    Wilkinson, Peter M
    Affiliation
    Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, England.
    Issue Date
    1990
    
    Metadata
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    Abstract
    Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.
    Citation
    Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer. 1990, 25 (6):435-9 Cancer Chemother. Pharmacol.
    Journal
    Cancer Chemotherapy and Pharmacology
    URI
    http://hdl.handle.net/10541/109856
    DOI
    10.1007/BF00686055
    PubMed ID
    2311172
    Type
    Article
    Language
    en
    ISSN
    0344-5704
    ae974a485f413a2113503eed53cd6c53
    10.1007/BF00686055
    Scopus Count
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    All Christie Publications
    All Paterson Institute for Cancer Research

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