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Pharmacokinetics of aerosol amphotericin B in rats
Y Niki1, E M Bernard, H J Schmitt
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Abstract:
The distributions of amphotericin B (AmB) in tissue were compared after intraperitoneal or aerosol administration. Rats were sacrificed 24 h after receiving single or repeated daily doses; AmB concentrations in tissues were determined by high-performance liquid chromatography. After intraperitoneal doses of 4 mg/kg of body weight per day for 7 days, mean concentrations of AmB were 122.7, 55.2, and 4.31 micrograms/g in the spleen, liver, and lung, respectively. After aerosol doses (aero-AmB) of 1.6 mg/kg per day, the mean concentrations of AmB in the lung were 2.79 micrograms/g after a single dose and 9.88 micrograms/g after four doses, while the drug was undetectable (less than 0.1 micrograms/g) in serum, spleen, liver, kidney, and brain. The half-life of elimination of AmB from the lungs was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aero-AmB per kg. Treatment with 60 mg of aero-AmB per kg was well tolerated and produced no histopathologic changes in the lungs. The aerosol route was much more efficient than the systemic route in delivering AmB to the lungs, and it limited the accumulation of AmB in other organs. Because AmB is eliminated slowly, infrequent dosing schedules can be used. These pharmacokinetic characteristics and its proven effectiveness in an animal model make aero-AmB a highly promising new method for the prevention of pulmonary aspergillosis. Aero-AmB should also be considered for use as an adjunct to intravenous AmB for treatment of fungal pneumonias.
Insights
Aerosol administration of amphotericin B (AmB) delivers the antifungal drug effectively to the lungs, minimizing systemic exposure. This promising new method, aerosolized AmB, allows for infrequent dosing and potential use in treating fungal lung infections.
Area of Science:
- Pharmacology
- Mycology
- Drug Delivery
Background:
- Amphotericin B (AmB) is a critical antifungal agent.
- Pulmonary fungal infections, such as aspergillosis, pose significant clinical challenges.
- Optimizing AmB delivery to target tissues is essential for efficacy and safety.
Purpose of the Study:
- To compare the tissue distribution of amphotericin B (AmB) following intraperitoneal versus aerosol administration in rats.
- To evaluate the pharmacokinetic profile and safety of aerosolized AmB (aero-AmB).
- To assess the potential of aero-AmB as a novel therapeutic strategy for pulmonary fungal infections.
Main Methods:
- Rats received single or repeated daily doses of AmB via intraperitoneal injection or aerosol inhalation.
- AmB concentrations in various tissues (spleen, liver, lung, serum, kidney, brain) were quantified using high-performance liquid chromatography.
- Pharmacokinetic parameters, including elimination half-life from the lungs, were determined.
- Histopathologic examination of lung tissue was performed to assess safety.
Main Results:
- Aerosol administration resulted in significantly higher AmB concentrations in the lungs compared to intraperitoneal dosing.
- Intraperitoneal AmB accumulated in the spleen and liver, whereas aero-AmB was undetectable in these organs and serum.
- The elimination half-life of AmB from the lungs was approximately 4.8 days after a single aerosol dose.
- Aero-AmB treatment was well-tolerated, with no observed histopathologic changes in the lungs.
Conclusions:
- Aerosolized AmB is a highly efficient route for delivering the drug to the lungs, surpassing systemic administration.
- This delivery method limits drug accumulation in non-target organs, potentially reducing toxicity.
- The favorable pharmacokinetic profile, including slow lung elimination and tolerability, supports infrequent dosing schedules.
- Aero-AmB presents a promising new approach for preventing pulmonary aspergillosis and may serve as an adjunct therapy for fungal pneumonias.