PT  - JOURNAL ARTICLE
AU  - S. M. Yule
AU  - D. Walker
AU  - M. Cole
AU  - L. McSorley
AU  - S. Cholerton
AU  - A. K. Daly
AU  - A.D.J. Pearson
AU  - A. V. Boddy
TI  - The Effect of Fluconazole on Cyclophosphamide Metabolism in Children
DP  - 1999 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 417--421
VI  - 27
IP  - 3
4099  - http://dmd.aspetjournals.org/content/27/3/417.short
4100  - http://dmd.aspetjournals.org/content/27/3/417.full
SO  - Drug Metab Dispos1999 Mar 01; 27
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics