Abstract |
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.
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Authors | Andreas H Groll, Diana Mickiene, Vidmantas Petraitis, Ruta Petraitiene, Raul M Alfaro, Christine King, Stephen C Piscitelli, Thomas J Walsh |
Journal | Antimicrobial agents and chemotherapy
(Antimicrob Agents Chemother)
Vol. 47
Issue 12
Pg. 3917-25
(Dec 2003)
ISSN: 0066-4804 [Print] United States |
PMID | 14638502
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Antifungal Agents
- Drug Combinations
- Electrolytes
- Liposomes
- beta 2-Microglobulin
- Deoxycholic Acid
- Nystatin
- Amphotericin B
- amphotericin B, deoxycholate drug combination
- Creatinine
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Topics |
- 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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