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Effect of variation in infusion time and macrophage blockade on organ uptake of amphotericin B-deoxycholate
L C Edmonds1, L Davidson, J S Bertino
1Department of Medicine, Mary Imogene Bassett Hospital, Cooperstown, New York 13326.
Abstract:
Amphotericin B is administered as a colloidal suspension due to its insolubility in water. Macrophages, particularly those in the liver, have been implicated as the predominant cell type responsible for the uptake of colloidal amphotericin B. We examined the effect of infusion time and macrophage function to confirm the role of the macrophage in the uptake of amphotericin B. Prolonged infusion time (24 h compared to 6 h) resulted in significantly less hepatic and splenic accumulation of amphotericin B. Blockade of macrophage function with methylpalmitate also resulted in significantly decreased hepatic and splenic uptake of amphotericin B. Uptake of amphotericin B by lung macrophages was not significantly affected by methylpalmitate. The area under the serum concentration versus time curve was significantly higher in the group that received methylpalmitate compared to either the 6 or 24 h amphotericin B infusion groups. These results suggest that fixed macrophages play an important part in the pharmacokinetics of amphotericin B, and that increasing drug solubility may alter the pharmacokinetics of amphotericin B.
Insights
Macrophages significantly impact amphotericin B (AMB) distribution. Blocking macrophage function or altering infusion time affects AMB accumulation, suggesting strategies to improve drug delivery and efficacy.
Area of Science:
- Pharmacology
- Immunology
- Drug Delivery
Background:
- Amphotericin B (AMB) is poorly water-soluble, necessitating administration as a colloidal suspension.
- Macrophages, especially in the liver, are believed to be primary sites for colloidal AMB uptake.
- Understanding AMB's cellular uptake is crucial for optimizing its therapeutic use.
Purpose of the Study:
- To investigate the influence of infusion duration on AMB pharmacokinetics.
- To confirm the role of macrophages in AMB uptake and distribution.
- To explore how modulating macrophage function affects AMB disposition.
Main Methods:
- Comparison of AMB accumulation in liver and spleen after 6-hour versus 24-hour infusions.
- Assessment of AMB uptake following macrophage blockade using methylpalmitate.
- Analysis of serum drug concentration-time profiles (AUC) in different treatment groups.
Main Results:
- Prolonged AMB infusion (24h vs 6h) led to reduced hepatic and splenic drug accumulation.
- Methylpalmitate blockade of macrophages significantly decreased hepatic and splenic AMB uptake.
- Macrophage blockade resulted in a higher area under the serum concentration-time curve (AUC) for AMB.
Conclusions:
- Fixed tissue macrophages play a critical role in the pharmacokinetics of colloidal amphotericin B.
- Altering infusion time impacts drug distribution, likely by influencing macrophage interaction.
- Strategies to enhance AMB solubility could potentially modify its pharmacokinetic profile and therapeutic outcomes.