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Uptake and intracellular activity of fluconazole in human polymorphonuclear leukocytes
Abstract:
The penetration of fluconazole into human polymorphonuclear leukocytes (PMNs) and tissue culture epithelial cells (McCoy) was evaluated. At different extracellular concentrations (0.5 to 10 mg/liter), fluconazole reached cell-associated concentrations greater than the extracellular ones in either human PMNs (intracellular concentration to extracellular concentration ratio, > or = 2.2) or McCoy cells (intracellular concentration to extracellular concentration ratio, > or = 1.3). The uptake of fluconazole by PMNs was rapid and reversible but was not energy dependent. The intracellular penetration of fluconazole was not affected by environmental pH or temperature. Ingestion of opsonized zymosan and opsonized Candida albicans did not significantly increase the amount of PMN-associated fluconazole. At therapeutic extracellular concentrations, the intracellular activity of fluconazole against C. albicans in PMNs was significantly lower than that of amphotericin B. It was concluded that fluconazole reaches high intracellular concentrations within PMNs but shows moderate activity against intracellular C. albicans in vitro.
Insights
Fluconazole penetrates human immune cells (PMNs) and epithelial cells, reaching higher intracellular concentrations. However, its in vitro activity against Candida albicans within PMNs is less effective than amphotericin B.
Area of Science:
- Pharmacology
- Cell Biology
- Mycology
Background:
- Fluconazole is a widely used antifungal agent.
- Understanding its intracellular penetration is crucial for optimizing therapy.
- Polymorphonuclear leukocytes (PMNs) play a key role in antifungal immunity.
Purpose of the Study:
- To evaluate the penetration of fluconazole into human PMNs and McCoy epithelial cells.
- To assess the factors influencing fluconazole uptake by PMNs.
- To compare the intracellular activity of fluconazole against Candida albicans in PMNs with amphotericin B.
Main Methods:
- Cells (human PMNs and McCoy cells) were exposed to varying extracellular concentrations of fluconazole.
- Intracellular and extracellular concentrations of fluconazole were measured.
- Factors such as pH, temperature, and phagocytosis were investigated for their effect on uptake.
- Intracellular activity against Candida albicans was assessed in PMNs.
Main Results:
- Fluconazole achieved higher intracellular concentrations than extracellular concentrations in both PMNs (ratio >= 2.2) and McCoy cells (ratio >= 1.3).
- PMN uptake of fluconazole was rapid, reversible, and independent of energy, pH, or temperature.
- Phagocytosis of opsonized zymosan or Candida albicans did not significantly enhance fluconazole association with PMNs.
- Intracellular fluconazole activity against Candida albicans in PMNs was significantly lower than that of amphotericin B.
Conclusions:
- Fluconazole effectively penetrates human PMNs and epithelial cells, reaching substantial intracellular levels.
- Despite high intracellular concentrations, fluconazole exhibits moderate in vitro activity against intracellular Candida albicans within PMNs.
- These findings suggest potential limitations of fluconazole for intracellular fungal infections mediated by PMNs.