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The effect of fluconazole on cyclophosphamide metabolism in children

Lookup NU author(s): Mike Cole, Professor Suzanne Cholerton, Professor Ann Daly, Professor Andrew Pearson, Professor Alan 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/m(2), 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 mu M (median 38 mu M). 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.


Publication metadata

Author(s): Yule, S. M., Walker, D., Cole, M., McSorley, L., Cholerton, S., Daly, A. K., Pearson, A. D. J., Boddy, A. V.

Publication type: Article

Publication status: Published

Journal: Drug Metabolism and Disposition

Year: 1999

Volume: 27

Issue: 3

Pages: 417-421

Print publication date: 01/03/1999

ISSN (print): 0090-9556

ISSN (electronic): 1521-009X

URL: http://dmd.aspetjournals.org/cgi/content/full/27/3/417


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