The effect of fluconazole on cyclophosphamide metabolism in children

Fluconazole is increasingly used in children receiving chemotherapy. Many o f these patients are being treated with cyclophosphamide, which must underg o 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 therap eutic effect of cyclophosphamide. To investigate this interaction, a retros pective case series of patients was chosen from a population of children wi th a previously established profile of cyclophosphamide metabolism. Twenty- two children who were not receiving other therapy known to influence drug m etabolism were selected and analyzed in terms of fluconazole treatment; of these, nine were receiving fluconazole and thirteen were identified as cont rols. Study design was not randomized. The plasma clearance of cyclophospha mide 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 character ize the interaction between fluconazole and cyclophosphamide in six human l iver microsomes. The concentration of fluconazole required to reduce the pr oduction of 4-hydroxycyclophosphamide to 50% of control values (IC50) varie d 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 t o determine whether this interaction reduces the therapeutic effect of cycl ophosphamide in clinical practice.