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Comparative Tissue Distribution and Elimination of Amphotericin B Colloidal Dispersion (Amphocil®) and Fungizone® After Repeated Dosing in Rats

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Abstract

The pharmacokinetic profiles of amphotericin B (AmB) after administration of Amphocil®, an AmB/cholesteryl sulfate colloidal dispersion (ABCD) and the micellar AmB/deoxycholate (Fungizone®) were compared after repeated dosing in rats. After administration of ABCD and Fungizone at an equal AmB dose (1 mg/kg), AmB concentrations in plasma and most tissues were lower for the ABCD dose, especially in the kidneys where reduced drug concentration correlated with reduced nephrotoxicity. In contrast, AmB concentrations in the liver were substantially higher when ABCD was administered; however, without an accompanying increase in hepato-toxicity. Daily administration of ABCD for 14 days did not lead to AmB accumulation in plasma; while a slight accumulation was observed after multiple administration of Fungizone. AmB was eliminated more slowly from the plasma and various tissues and urinary and fecal recoveries of AmB were reduced after ABCD administration. These results suggest that ABCD may be stored in tissues in a form that is less toxic and is eliminated from the systemic circulation by a different mechanism than the free and protein-bound AmB in plasma. AmB accumulation in the spleen was observed when higher doses of ABCD (5 mg/kg) were administered, which could be due to saturation of hepatic uptake of AmB. Comparison of spleen concentrations of AmB between ABCD and Fungizone® at 5 mg/kg AmB doses was not possible because of Fungizone's toxicity in rats. In all other organs, AmB concentrations reached or approached a steady state within two weeks of dosing with ABCD. Urinary and fecal clearances of AmB were not different between ABCD and Fungizone administration. In summary, the distribution and elimination characteristics of AmB in rats were substantially altered when it was administered as ABCD in comparison to Fungizone. Nephrotoxicity of AmB in rats was reduced after administration of ABCD apparently because of the altered tissue distribution pattern. Thus, ABCD (Amphocil®) may be a clinically beneficial formulation of AmB in patients with systemic fungal infections.

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Author notes

  1. Robert M. Fielding

    Present address: NeXagen, Inc., 2860 Wilderness Place, Boulder, CO, 80301

Authors and Affiliations

  1. Division of Pharmacokinetics and Drug Metabolism, Burroughs Wellcome Co., Research Triangle Park, NC, 27709

    Laurence H. Wang

  2. Liposome Technology, Inc., 1050 Hamilton Court, Menlo Park, CA, 94025

    Robert M. Fielding & Luke S. S. Guo

  3. Division of Pharmaceutics, School of Pharmacy, the University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599

    Philip C. Smith

Authors
  1. Laurence H. Wang
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  2. Robert M. Fielding
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  3. Philip C. Smith
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  4. Luke S. S. Guo
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Wang, L.H., Fielding, R.M., Smith, P.C. et al. Comparative Tissue Distribution and Elimination of Amphotericin B Colloidal Dispersion (Amphocil®) and Fungizone® After Repeated Dosing in Rats. Pharm Res 12, 275–283 (1995). https://doi.org/10.1023/A:1016243313027

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  • DOI: https://doi.org/10.1023/A:1016243313027

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