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Lookup NU author(s): Emerita Professor Suzanne Cholerton,
Professor Ann Daly,
Professor Andrew Pearson,
Professor Alan Boddy
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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.
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
Print publication date: 01/03/1999
ISSN (print): 0090-9556
ISSN (electronic): 1521-009X