Comparative drug disposition, urinary pharmacokinetics, and renal effects of multilamellar liposomal nystatin and amphotericin B deoxycholate in rabbits.

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 (Cmax) (17 to 56 microg/ml for LNYS versus 3.36 microg/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 microg.h/ml for LNYS versus 12 microg.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 < or =8-fold-smaller volume of distribution at steady state (P=0.002). Urinary drug concentration data revealed a > or =10-fold-higher Cmax (16 to 10 microg/ml for LNYS versus 0.96 microg/ml for DAMB; P=0.015) and a 4- to 7-fold-greater AUC(0-24) (63 to 35 microg.h/ml for LNYS versus 8.9 microg.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.
AuthorsAndreas H Groll, Diana Mickiene, Vidmantas Petraitis, Ruta Petraitiene, Raul M Alfaro, Christine King, Stephen C Piscitelli, Thomas J Walsh
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 47 Issue 12 Pg. 3917-25 (Dec 2003) ISSN: 0066-4804 [Print] United States
PMID14638502 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Antifungal Agents
  • Drug Combinations
  • Electrolytes
  • Liposomes
  • beta 2-Microglobulin
  • Deoxycholic Acid
  • Nystatin
  • Amphotericin B
  • amphotericin B, deoxycholate drug combination
  • Creatinine
  • Amphotericin B (administration & dosage, adverse effects, pharmacokinetics)
  • Animals
  • Antifungal Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Area Under Curve
  • Creatinine (metabolism)
  • Deoxycholic Acid (administration & dosage, adverse effects, pharmacokinetics)
  • Drug Combinations
  • Electrolytes (urine)
  • Female
  • Kidney Function Tests
  • Liposomes
  • Models, Biological
  • Nystatin (administration & dosage, adverse effects, pharmacokinetics)
  • Rabbits
  • Tissue Distribution
  • Urodynamics (drug effects)
  • beta 2-Microglobulin (metabolism)

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