Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte-macrophage progenitor cells in vitro.
We studied the inhibitory effects on colony formation by granulocyte-macrophage colony forming units (cfu-gm) of eight azole antifungal agents in vitro. All agents, except fluconazole, inhibited colony formation dose-dependently with 50% inhibitory concentrations (IC50) in the range of 0.78-49 micromol/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 miconazole, 6.17 mg/L for econazole, 6.27 mg/L for ketoconazole and 8.38 mg/L for oxiconazole. The IC50 of itraconazole for human cfu-gm in vitro was similar to the plasma level of this drug recommended for 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 (> or =400 mg) doses, whereas fluconazole failed to reduce colony formation by 50% even at 100 mg/L, a concentration not reached in vivo even after extremely high doses (2000 mg/day). To most of the drugs studied, murine progenitor cells seemed to be less sensitive than the human ones. There was, however, a close correlation between the murine and human log IC50 values of the drugs (r2 = 0.964, P< 0.001), suggesting that cultures of murine bone marrow may be suitable to predict the in-vitro toxicity of azole antifungals to human cfu-gm.
Benko
I
I
Department of Pharmacology, University Medical School, Debrecen, Hungary. benko@king.pharmacol.dote.hu
Hernádi
F
F
Megyeri
A
A
Kiss
A
A
Somogyi
G
G
Tegyey
Z
Z
Kraicsovits
F
F
Kovács
P
P
D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001393:Azoles / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003022:Clotrimazole / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004464:Econazole / Q000633:toxicity; D005260:Female; D015725:Fluconazole / Q000633:toxicity*; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008825:Miconazole / Q000633:toxicity; D013045:Species Specificity; D013234:Stem Cells / Q000187:drug effects*
D000935:Antifungal Agents; D001393:Azoles; D007093:Imidazoles; D004464:Econazole; D008825:Miconazole; D015725:Fluconazole; C022155:oxiconazole; D003022:Clotrimazole; D007654:Ketoconazole