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

Abstract

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.

Long term control of hypercortisolism with fluconazole: case report and in vitro studies

“…In a primary rat hepatocyte culture system allowing the assessment of plasma membrane integrity and mitochondrial as well as lysosomal stability fluconazole was shown to exert considerably less cytotoxic effects than ketoconazole (17). Similar results were also seen in human granulocyte-macrophage progenitor cells in vitro (18).…”

In vivo toxicity of a new antifungal agent 2,4-dithiophenoxy-1-iodo-4-bromo benzene: a follow up on our in vitro study / In vivo toksičnost novoga antimikotika 2,4-ditiofenoksi-1-jodo-4-bromobenzena: proširenje in vitro istraživanja

“…This may point to fluconazole's greater toxicity. Fluconazole is known to lower the expression of various cytokine genes because of its lipophilic character (17). The increased glomerular diameter and volume in the fluconazole group seem to confirm the migration of neutrophils (18).…”

New drugs and vaccines for drug-resistantMycobacterium tuberculosisinfections

“…The MIC 90 was 0.12 µg/ml, whereas the minimum bactericidal concentration was 0.125 µg/ml for both drugs, demonstrating their excellent bactericidal activities [81]. Ex vivo studies on mice splenocytes following exposure to clotrimazole and econazole confirmed the good tolerance and synergistic effects of these drug [82]. Further in vivo analyses have determined that econazole is well tolerated in combination therapies and equipotent to RIF in the treatment of murine TB [83].…”