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Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions
A Wildfeuer1, H Laufen, T Zimmermann
1Department of Research and Development, Pfizer/Mack, Illertissen, Germany.
Abstract:
The concentrations of azithromycin in polymorphonuclear leukocytes (PMNLs), monocytes, erythrocytes, and plasma were measured in six healthy volunteers after the last treatment of a 3-day regimen of 500 mg once daily. Marked enrichment of azithromycin was found in PMNLs and monocytes. The drug concentrations after the last dose amounted to 114 +/- 43 (mean +/- standard deviation) mg/liter at 12 h in PMNLs and 34 +/- 17 mg/liter at 6 h in monocytes. Fourteen days thereafter, azithromycin was still detectable in the PMNLs at 53 +/- 34 mg/liter and in the monocytes at 1 +/- 2 mg/liter, although the drug was no longer detectable in plasma (< 0.02 mg/liter). Maximum drug concentrations for azithromycin in plasma (0.40 +/- 0.30 mg/liter) and erythrocytes (0.15 +/- 0.05 mg/liter) at 3 h after the last administration were much lower and occurred earlier than those observed in the phagocytic cells. The mean enrichment factors (cellular/extracellular ratios) of azithromycin in phagocytes relative to plasma came to 231 +/- 150 and 3,924 +/- 584 at 3 and 120 h, respectively, for PMNLs and 83 +/- 55 and 523 +/- 285 at 3 and 120 h for monocytes, respectively, after the last dose. The phagocytosis tests with PMNLs separated from the blood of volunteers at various times after the last treatment confirmed the enhanced intracellular activity of these cells against staphylococci.
Insights
Azithromycin concentrates significantly in white blood cells like polymorphonuclear leukocytes (PMNLs) and monocytes, persisting long after plasma levels drop. This cellular accumulation enhances the drug's infection-fighting capabilities.
Area of Science:
- Pharmacology
- Infectious Diseases
- Cell Biology
Background:
- Azithromycin is a widely used antibiotic.
- Understanding its distribution in blood cells is crucial for optimizing therapy.
- Phagocytic cells play a key role in fighting bacterial infections.
Purpose of the Study:
- To quantify azithromycin concentrations in various blood components.
- To determine the cellular enrichment of azithromycin in phagocytes.
- To assess the impact of cellular accumulation on antimicrobial activity.
Main Methods:
- Healthy volunteers received a 3-day azithromycin regimen.
- Blood samples were analyzed for azithromycin levels in PMNLs, monocytes, erythrocytes, and plasma.
- Phagocytosis assays were performed using isolated PMNLs.
Main Results:
- Azithromycin showed marked enrichment in PMNLs and monocytes, with high concentrations persisting for days.
- Cellular drug levels were significantly higher and longer-lasting than plasma levels.
- Enrichment factors in phagocytes relative to plasma were substantial, indicating significant intracellular accumulation.
- Enhanced intracellular azithromycin correlated with increased activity against staphylococci.
Conclusions:
- Azithromycin accumulates significantly in human phagocytic cells (PMNLs and monocytes).
- This intracellular accumulation contributes to sustained antimicrobial activity.
- The findings support azithromycin's efficacy in treating infections involving these cellular compartments.