[Effect of imidazole antifungal agents on colony formation by murine bone marrow CFUc (colony forming units in culture].

In spite of modern antifungal therapy, the prognosis of systemic mycoses in neutropenic patients is usually poor without recovery of neutrophil counts. So, even a minor myelotoxicity might be a significant disadvantage of any drug used for the treatment of neutropenic patients with fungal infections. Since "Colony Forming Units in culture" (CFUc), the common progenitors of granulocytes and macrophages, are supposed to be a major target of agents damaging bone marrow, we studied the inhibitory effect of four imidazole antifungal drugs to colony formation by murine CFUc in vitro. Clotrimazole, econazole, miconazole or ketoconazole were added to soft agar bone marrow cell cultures at final concentrations of 1 to 30 mg/l at the beginning of the 7 day culture period. A dose-dependent inhibitory effect on colony formation by CFUc was observed with all imidazole drugs studied. The 50 percent inhibitory concentrations (IC50s) were 3.54 mg/l for clotrimazole, 8.07 mg/l for econazole, 14.04 mg/l for miconazole, and 16.11 mg/l for ketoconazole. Human pharmacokinetic data available in the literature on these drugs may help to assess the potential in vivo relevance of our results. The serum levels of clotrimazole and econazole, even after oral administration, remain lower than those found to inhibit colony formation by murine bone marrow in our experiments. Taking into consideration that clotrimazole and econazole are used only topically in the clinical practice, our data do not suggest any clinically significant suppression of bone marrow by these two drugs. Intravenous administration of high doses of miconazole, however, may result in serum concentrations approaching the IC50 for colony formation by murine bone marrow cells in vitro. As for ketoconazole, it may suppress the proliferation of murine bone marrow progenitor cells in vitro at concentrations produced in vivo by high doses (12.5-18 and 30-50 mg/l after 400 or 600 mg, respectively). The serum levels produced by a daily dose of 200 mg ketoconazole (about 4 mg/l), however, did not reduce significantly the number of colonies in murine bone marrow cultures. Our present results warrant further studies of the myelotoxicity of miconazole and ketoconazole in vivo in mice with neutropenia induced by cytostatic agents.