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 (C
max) (17 to 56μ
g/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 (AUC0-24) (17 to 77μ
g · h/ml for LNYS versus 12μ
g · 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 0.96μ
g/ml for DAMB; P = 0.015) and a 4- to
7-fold-greater AUC0-24 (63 to 35μ
g · h/ml for LNYS versus 8.9μ
g · h/ml for DAMB; P =
0.015) following the administration of LNYS, with a dose-dependent
decrease in the dose-normalized AUC0-24 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.
Activity of a Heat-Induced Reformulation of Amphotericin B Deoxycholate (Fungizone) against Leishmania donovani
