Fluconazole Cyclophosphamide

Allopurinol, barbiturates, carbamazepine, cephalosporins, cyclophosphamide, ethambutol, fluconazole, ibuprofen, lamotrigine, macrolides, nitrofurantoin, penicillins, phenytoin, propranolol, quinolones, sulfonamide antimicrobials, sulindac, tetracyclines, thiazides, valproic acid, and vancomycin... 

Shibata S, Kami M, Kanda Y, Machida U, Iwata H, Kishi Y, Takeshita A, Miyakoshi S, Ueyama J, Morinaga S, Mutou Y. Acute adrenal failure associated with fluconazole after administration of high-dose cyclophosphamide. Am J Hematol 2001 66(4) 303-5. 

Cyclophosphamide is a prodrug that requires cjdochrome P450 -dependent hepatic activation to produce alkylating species and several inactive by-products. However, very few metabolic interactions involving cyclophosphamide have been reported. In a retrospective study of 22 children treated with cyclophosphamide for cancer or bone marrow transplantation, cyclophosphamide clearance was significantly lower in nine patients taking fluconazole compared with 13 patients not taking it (77). In vitro studies in human hver microsomes confirmed that the rate of 4-hydroxylation of cyclophosphamide was inhibited by fluconazole. 

Yule SM, Walker D, Cole M, McSorley L, Cholerton S, Daly AK, Pearson AD, Boddy AV. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos 1999 27(3) 417-21. 

Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to produce alkylating species, which are cytotoxic, and the extent of cyclophosphamide metabolism correlates with both treatment efficacy and toxicity. In vitro studies in six human liver microsomes showed that the IC50 of fluconazole for reduction of 4-hydroxycyclo-phosphamide production was 9-80 pmol/1 (93). 

A retrospective study in 22 children with cancers addressed the potential interaction between fluconazole and cyclophosphamide. Children with an established profile of cyclophosphamide metabolism who were not receiving other drugs known to affect drug metabolism were selected 9 were taking fluconazole and 13 were controls. The plasma clearance was significantly lower in patients taking concomitant fluconazole (2.4 versus 4.2 1/ hour/m ). It is unclear whether this interaction is associated with a reduction in the therapeutic efficacy of cyclophosphamide. 

Fluconazole and itraconazole inhibit the metabolism of cyclophosphamide. There is some evidence that, compared with fluconazole, itraconazole might increase cyclophosphamide toxicity. Ketoconazole inhibits the metabolism of ifosfamide. This did not improve the ratio of active to inactive-toxic metabolites, and the possibility remains that ifosfamide efficacy could be reduced. 

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