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Research ArticleArticle

The Effect of Fluconazole on Cyclophosphamide Metabolism in Children

S. M. Yule, D. Walker, M. Cole, L. McSorley, S. Cholerton, A. K. Daly, A.D.J. Pearson and A. V. Boddy
Drug Metabolism and Disposition March 1999, 27 (3) 417-421;
S. M. Yule
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D. Walker
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M. Cole
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L. McSorley
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S. Cholerton
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A. K. Daly
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A.D.J. Pearson
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A. V. Boddy
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Abstract

Fluconazole is increasingly used in children receiving chemotherapy. Many of these patients are being treated with cyclophosphamide, which must undergo hepatic metabolism to produce active alkylating species. As a consequence of the cytochrome P-450 inhibitory properties of fluconazole, a potential interaction exists between these two agents that could influence the therapeutic effect of cyclophosphamide. To investigate this interaction, a retrospective case series of patients was chosen from a population of children with a previously established profile of cyclophosphamide metabolism. Twenty-two children who were not receiving other therapy known to influence drug metabolism were selected and analyzed in terms of fluconazole treatment; of these, nine were receiving fluconazole and thirteen were identified as controls. Study design was not randomized. The plasma clearance of cyclophosphamide was lower in patients receiving fluconazole [mean(SD) 2.4(0.71) versus 4.2(1.2) l/h/m2, p = .001]. In vitro studies were performed to characterize the interaction between fluconazole and cyclophosphamide in six human liver microsomes. The concentration of fluconazole required to reduce the production of 4-hydroxycyclophosphamide to 50% of control values (IC50) varied between 9 and 80 μM (median 38 μM). Further studies of the effect of fluconazole on 4-hydroxycyclophosphamide production in vivo are warranted to determine whether this interaction reduces the therapeutic effect of cyclophosphamide in clinical practice.

Footnotes

  • Send reprint requests to: Dr. S. M. Yule, Department of Haematology, Yorkhill NHS Trust, Glasgow G3 8SJ, United Kingdom.

  • This work was supported by the The Tyneside Leukaemia Research Fund and the North of England Childrens Cancer Research Fund.

  • Abbreviations used are::
    P-450s
    cytochrome P-450 enzymes
    DCCP
    dechloroethylcyclophosphamide
    CX
    carboxyphosphamide
    mesna sodium
    2-mercaptoethane sulphonate
    AUC
    area under the concentration-time curve
    • Received May 26, 1998.
    • Accepted November 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (3)
Drug Metabolism and Disposition
Vol. 27, Issue 3
1 Mar 1999
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Research ArticleArticle

The Effect of Fluconazole on Cyclophosphamide Metabolism in Children

S. M. Yule, D. Walker, M. Cole, L. McSorley, S. Cholerton, A. K. Daly, A.D.J. Pearson and A. V. Boddy
Drug Metabolism and Disposition March 1, 1999, 27 (3) 417-421;

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Research ArticleArticle

The Effect of Fluconazole on Cyclophosphamide Metabolism in Children

S. M. Yule, D. Walker, M. Cole, L. McSorley, S. Cholerton, A. K. Daly, A.D.J. Pearson and A. V. Boddy
Drug Metabolism and Disposition March 1, 1999, 27 (3) 417-421;
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