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Antimicrobial Agents and Chemotherapy, July 2001, p. 2060-2063, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2060-2063.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Heat Treatment of Amphotericin B Modifies Its Serum Pharmacokinetics, Tissue Distribution, and Renal Toxicity following Administration of a Single Intravenous Dose to Rabbits

Evan H. Kwong,1 Manisha Ramaswamy,1 Emily A. Bauer,2 Scott C. Hartsel,2 and Kishor M. Wasan1,*

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3,1 and Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, Wisconsin2

Received 9 October 2000/Returned for modification 24 February 2001/Accepted 29 March 2001

The purpose of this investigation was to determine the serum pharmacokinetics, tissue distribution, and renal toxicity of amphotericin B (AmpB) following administration of a single intravenous dose (1 mg/kg of body weight) of Fungizone (FZ) and a heat-treated form of FZ (HFZ) to New Zealand White female rabbits. FZ solutions were heated at 70°C for 20 min to produce HFZ. Blood samples were obtained before drug administration and serially thereafter. After collection of the 48-h blood sample, each rabbit was humanely sacrificed and the right kidney, spleen, lungs, liver, and heart were harvested for AmpB analysis. Serum creatinine levels were measured before and 10 h after drug administration. AmpB concentrations in the serum and tissues were analyzed using high-performance liquid chromatography. FZ administration to rabbits resulted in a greater-than-50% increase in serum creatinine concentrations compared to baseline. However, HFZ administration resulted in no difference in serum creatinine concentrations compared to baseline. The AmpB area under the concentration-time curve (AUC) after HFZ administration was significantly lower than the AmpB AUC in rabbits administered FZ. However, AmpB systemic total body clearance was significantly greater in rabbits administered HFZ than in rabbits administered FZ without any differences in volume of distribution at steady state. Kidney tissue AmpB concentrations, although not significantly different, were greater in rabbits administered FZ than in rabbits administered HFZ. Likewise, lung and spleen AmpB concentrations, although not significantly different, were greater in rabbits administered FZ than in rabbits administered HFZ. However, liver AmpB concentrations were significantly lower in rabbits administered FZ than in rabbits administered HFZ. No significant differences in heart AmpB concentration between rabbits administered FZ and those given HFZ were found. These findings suggest that the pharmacokinetics, tissue distribution, and renal toxicity of AmpB are modified following administration of HFZ. HFZ could be an improved low-cost AmpB drug delivery system that has a potentially higher therapeutic index than FZ.

* Corresponding author. Mailing address: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: (604) 822-4889. Fax: (604) 822-3035. E-mail: Kwasan{at}interchange.ubc.ca.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2060-2063, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2060-2063.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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