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Antimicrobial Agents and Chemotherapy, December 2003, p. 3917-3925, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3917-3925.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Comparative Drug Disposition, Urinary Pharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatin and Amphotericin B Deoxycholate in Rabbits

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,¹ Pharmacokinetics Research Laboratory, Pharmacy Department,³ Department of Clinical Pathology, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland,⁴ Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Federal Republic of Germany²

Received 27 January 2003/ Returned for modification 9 June 2003/ Accepted 31 August 2003

The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C_max) (17 to 56 µg/ml for LNYS versus 3.36 µg/ml for DAMB; P < 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC_0-24) (17 to 77 µg · h/ml for LNYS versus 12 µg · h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P = 0.013) and a 8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a 10-fold-higher C_max (16 to 10 µg/ml for LNYS versus 0.96 µg/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC_0-24 (63 to 35 µg · h/ml for LNYS versus 8.9 µg · h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized AUC_0-24 in urine (P = 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P, <0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes.

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