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Tissue distribution of amphotericin B lipid complex in laboratory animals
S J Olsen1, M R Swerdel, B Blue
1Department of Microbiology, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000.
Abstract:
Amphotericin B lipid complex (ABLC), under development for the treatment of serious fungal disease, is not a true liposome but a complex of amphotericin B, dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with a particle size range of 1.6-6.0 microns. Tissue distribution of ABLC was determined in mice and rats after i.v. or i.p. administration. ABLC resembles typical liposomal preparations with amphotericin B concentrating in the reticuloendothelial system. After a single i.v. treatment with ABLC, amphotericin B was present in high concentrations in liver, lung and spleen of mice and rats while plasma levels were consistently low. Mouse liver contained 48% of the administered dose 1 h after treatment and always contained the largest amount of amphotericin B after ABLC treatment. In mice treated once daily for 7 consecutive days with 10 mg kg-1 ABLC, liver amphotericin B concentration reached 377 micrograms g-1. Tissue concentrations of amphotericin B were substantially lower when ABLC was given i.p. instead of i.v. with reticuloendothelial tissues containing 2- to 7-fold more after i.v. treatment. Animals treated with 10 mg kg-1 ABLC for 14 consecutive days showed no overt signs of toxicity and had only transient changes in liver and kidney function after treatment.
Insights
Amphotericin B lipid complex (ABLC) concentrates in the liver, spleen, and lungs after intravenous administration in animal models. This antifungal agent shows favorable tissue distribution with minimal toxicity in preclinical studies.
Area of Science:
- Pharmacology
- Mycology
- Drug Delivery Systems
Background:
- Amphotericin B lipid complex (ABLC) is an investigational antifungal agent for serious fungal infections.
- ABLC is a complex of amphotericin B with lipids, not a true liposome, with a particle size of 1.6-6.0 microns.
Purpose of the Study:
- To determine the tissue distribution of amphotericin B after administration of amphotericin B lipid complex (ABLC).
- To evaluate the toxicity profile of ABLC in preclinical animal models.
Main Methods:
- Tissue distribution of ABLC was assessed in mice and rats following intravenous (i.v.) or intraperitoneal (i.p.) administration.
- Amphotericin B concentrations were measured in various tissues and plasma over time.
- Toxicity was evaluated through clinical signs and liver/kidney function tests after repeated dosing.
Main Results:
- Following i.v. administration, amphotericin B predominantly accumulated in the reticuloendothelial system, particularly the liver, lung, and spleen.
- Plasma concentrations of amphotericin B remained consistently low after i.v. ABLC treatment.
- i.v. administration resulted in significantly higher tissue concentrations compared to i.p. administration.
- Repeated daily dosing of ABLC for 14 days showed no overt toxicity and only transient changes in liver and kidney function.
Conclusions:
- Amphotericin B lipid complex exhibits favorable tissue distribution, concentrating in key organs of the reticuloendothelial system after i.v. administration.
- The i.v. route of administration leads to enhanced tissue drug levels compared to the i.p. route.
- ABLC demonstrates a promising safety profile in preclinical studies, with minimal toxicity observed even after prolonged treatment.