Affiliation:
1. Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1and
2. Pharmacokinetics Research Laboratory, Pharmacy Department, Warren Grant Magnuson Clinical Center,2 National Institutes of Health, Bethesda, Maryland 20892
Abstract
ABSTRACT
The plasma pharmacokinetics of multilamellar liposomal nystatin were studied in normal, catheterized rabbits after single and multiple daily intravenous administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of liposomal nystatin were measured as those of nystatin by a validated high-performance liquid chromatography method, and plasma concentration data were fitted into a two-compartment open model. Across the investigated dosage range, liposomal nystatin demonstrated nonlinear kinetics with more than proportional increases in the AUC
0–24
and decreasing clearance, consistent with dose-dependent tissue distribution and/or a dose-dependent elimination process. After single-dose administration, the mean
C
max
increased from 13.07 μg/ml at 2 mg/kg to 41.91 μg/ml at 6 mg/kg (
P
< 0.001); the AUC
0–24
changed from 11.65 to 67.44 μg · h/ml (
P
< 0.001), the
V
d
changed from 0.205 to 0.184 liters/kg (not significant), the CL
t
from 0.173 to 0.101 liters/kg · h (
P
< 0.05), and terminal half-life from 0.96 to 1.51 h (
P
< 0.05). There were no significant changes in pharmacokinetic parameters after multiple dosing over 14 days. Assessment of tissue concentrations of nystatin near peak plasma levels after multiple dosing over 15 days revealed preferential distribution to the lungs, liver, and spleen at that time point. Substantial levels were also found in the urine, raising the possibility that renal excretion may play a significant role in drug elimination. Liposomal nystatin administered to rabbits was well tolerated and displayed nonlinear pharmacokinetics, potentially therapeutic peak plasma concentrations, and substantial penetration into tissues. Pharmacokinetic parameters were very similar to those observed in patients, thus validating results derived from infection models in the rabbit and allowing inferences to be made about the treatment of invasive fungal infections in humans.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference27 articles.
1. History of antifungal therapy.;Andriole V. T.;Infect. Dis. Clin. Pract.,1998
2. Carrier effects on biological activity of amphotericin B
3. Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources Commission on Life Sciences National Research Council
Guide for the care and use of laboratory animals.
1996
National Academy Press
Washington D.C.
4. D'Argenio
D. Z.
Schumitzky
A.
Adapt II user's guide. Biomedical Simulations Resource
1990
University of Southern California
Los Angeles Calif
5. Dose Range Evaluation of Liposomal Nystatin and Comparisons with Amphotericin B and Amphotericin B Lipid Complex in Temporarily Neutropenic Mice Infected with an Isolate of
Aspergillus fumigatus
with Reduced Susceptibility to Amphotericin B
Cited by
23 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献