Biodistribution of amphotericin B when delivered through cholesterol hemisuccinate vesicles in normal and A. fumigatus infected mice.
OBJECTIVE
This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmB(DOC)).


METHODS
ABCV (12 mg/kg wt) and AmB(DOC) (2 mg/kg wt) were intravenously administered to normal and A. fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points.


RESULTS
It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmB(DOC) significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmB(DOC) (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmB(DOC) administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice.


CONCLUSIONS
Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.
Saxena
S
S
Department of Biochemistry, University of Delhi, New Delhi, India.
Ghosh
P C
PC
D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001228:Aspergillosis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D001232:Aspergillus fumigatus; D002021:Buffers; D002788:Cholesterol Esters / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003840:Deoxycholic Acid / Q000008:administration & dosage; D003902:Detergents / Q000008:administration & dosage; D004337:Drug Carriers; D004355:Drug Stability; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013535:Suspensions; D014018:Tissue Distribution
D000935:Antifungal Agents; D002021:Buffers; D002788:Cholesterol Esters; D003902:Detergents; D004337:Drug Carriers; D013535:Suspensions; D003840:Deoxycholic Acid; D000666:Amphotericin B; C013440:cholesteryl succinate