Comparison of the toxicity of fluconazole and other azole antifungal drugsto murine and human granulocyte-macrophage progenitor cells in vitro

We studied the inhibitory effects on colony formation by granulocyte-macrop hage colony forming units (cfu-gm) of eight azole antifungal agents in vitr o. All agents, except fluconazole, inhibited colony formation dose-dependen tly with 50% inhibitory concentrations (IC50) in the range of 0.78-49 mu mo l/L in cultures of murine and human bone marrow. For human cells, the IC50 values were 0.553 mg/L for itraconazole, 1.24 mg/L for saperconazole, 2.58 mg/L for clotrimazole, 5.33 mg/L for miconatole, 6.17 mg/L for econazole, 6 .27 mg/L for ketocanazole and 8.38 mg/L for oxiconazole. The IC50 of itraco nazole for human cfu-gm in vitro was similar to the plasma level of this dr ug recommended far systemic antifungal therapy (>0.5 mg/L) thus indicating the potential clinical relevance of our data. The IC50 of ketoconazole for human cfu-gm in vitro may be exceeded by plasma levels produced in vivo by high (greater than or equal to 400 mg) doses, whereas fluconazole failed to reduce colony formation by 50% even at 100 mg/L, a concentration not reach ed in vivo even after extremely high doses (2000 mg/day). To most of the dr ugs studied, murine progenitor cells seemed to be less sensitive than the h uman ones. There was, however, a close correlation between the murine and h uman log IC50 values of the drugs (r(2) = 0.964, P < 0.001), suggesting tha t cultures of murine bone marrow may be suitable to predict the in-vitro to xicity of azole antifungals to human cfu-gm.