Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte–macrophage progenitor cells in vitro
Open accessAbstract
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.
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Azoles exhibit a certain degree of toxicity that has already been demonstrated.
“Nevertheless, in comparison, azoles exhibit a certain degree of toxicity that has been already demonstrated.5,19”
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- Authors
- Benkoo, I.
- Affiliations
- University of Debrecen (HU)
- Corresponding author
- Benkoo, I.
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-05-01
- Volume
- 43
- Issue
- 5
- Pages
- 675-681
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2117988795
- Cited by
- 31
- References
- 23
- Citations by year
- 2025: 3 · 2024: 1 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 2 · 2013: 4 · 2012: 2
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- fluconazole, azole antifungals, CFU-GM, myelosuppression, bone marrow progenitor cells, colony formation inhibition, itraconazole, ketoconazole, clotrimazole, miconazole, econazole, oxiconazole, in vitro toxicity prediction, dose-dependent toxicity
- MeSH terms
- Animals, Antifungal Agents, Azoles, Bone Marrow, Cells, Cultured, Clotrimazole, Dose-Response Relationship, Drug, Econazole, Female, Granulocytes, Hematopoietic Stem Cells, Humans, Imidazoles, Ketoconazole, Macrophages, Male, Miconazole, Species Specificity, Stem Cells, Fluconazole, Inhibitory Concentration 50, Mice
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