title: Comparative drug disposition, urinary pharmacokinetics, and renal effects of multilamellar liposomal nystatin and amphotericin B deoxycholate in rabbits.
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.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Diana
authors.initials: D
authors.lastname: Mickiene
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Raul M
authors.initials: RM
authors.lastname: Alfaro
authors.forename: Christine
authors.initials: C
authors.lastname: King
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003404:Creatinine / Q000378:metabolism; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004573:Electrolytes / Q000652:urine; D005260:Female; D007677:Kidney Function Tests; D008081:Liposomes; D008954:Models, Biological; D009761:Nystatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011817:Rabbits; D014018:Tissue Distribution; D014563:Urodynamics / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D004573:Electrolytes; D008081:Liposomes; D001613:beta 2-Microglobulin; D003840:Deoxycholic Acid; D009761:Nystatin; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D003404:Creatinine