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