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Antimicrobial Agents and Chemotherapy, March 1999, p. 520-524, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Effect of Fasting on Temporal Variation in the
Nephrotoxicity of Amphotericin B in Rats
Michel
LeBrun,1
Louis
Grenier,1
Michel G.
Bergeron,1
Louise
Thibault,2
Gaston
Labrecque,1,3 and
Denis
Beauchamp1,*
Centre de Recherche en Infectiologie,
Faculté de Médecine,1 and
Faculté de Pharmacie,3
Université Laval, Sainte-Foy, Québec, Canada G1V 4G2,
and School of Dietetics and Human Nutrition, Macdonald
Campus of McGill University, Montréal, Québec, Canada H9X
3V92
Received 11 June 1998/Returned for modification 12 September
1998/Accepted 20 December 1998
 |
ABSTRACT |
Evidence for temporal variation in the nephrotoxicity of
amphotericin B was recently reported in experimental animals. The role
of food in these variations was determined by studying the effect of a
short fasting period on the temporal variation in the renal toxicity of
amphotericin B. Twenty-eight normally fed and 28 fasted female
Sprague-Dawley rats were used. Food was available ad libitum to the fed
rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals.
Water was available ad libitum to both groups of rats, which were
maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion
of renal enzyme and the serum creatinine and blood urea nitrogen (BUN)
levels at the time of the maximal (0700 h) or the minimal (1900 h)
nephrotoxicity after the intraperitoneal administration of a single
dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of
body weight; treated group) to the rats. The nephrotoxicities obtained
after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed
animals, the 24-h urinary excretion of
N-acetyl-
-D-glucosaminidase and
-galactosidase was significantly higher when amphotericin B was
injected at 0700 and 1900 h. The excretion of these two enzymes
was reduced significantly (P < 0.05) in fasting
rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also
significantly higher (P < 0.05) in fed animals
treated at 0700 h than in fed animals treated at 1900 h.
Fasting reduced significantly (P < 0.05) the
increase in the serum creatinine level, and this effect was larger in
the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher
(P < 0.05) in the renal cortexes of fed rats
than in those of fasted animals, but there was no difference according
to the time of injection. These results demonstrated that fasting
reduces the nephrotoxicity of amphotericin B and that food availability
is of crucial importance in the temporal variation in the renal
toxicity of amphotericin B in rats.
| |
INTRODUCTION |
Amphotericin B is a polyene
macrolide antifungal agent with a broad spectrum of activity. It
remains the most effective agent for the treatment of serious systemic
mycoses (11, 13, 23). The amphipathic property of the
amphotericin B chemical structure facilitates its binding to sterols of
the cell membrane, which induces disruption of the membrane's
integrity and cell death (4, 6). Although this antifungal
agent binds preferentially to ergosterol (the sterol of the fungal cell
wall), it also binds to cholesterol (the sterol of mammalian cell
membranes) (6, 12, 28). Despite its high nephrotoxic
potential and the recent introduction of newer antifungal agents,
amphotericin B remains the drug of choice for the treatment of severe
systemic fungal infections (10, 11, 13, 29).
The clinical use of amphotericin B is limited by a dose-dependent renal
toxicity that is reported to be found in up to 80% of treated patients
(13, 25). The clinical presentation of nephrotoxicity
includes azotemia, renal tubular acidosis, impairment of the ability to
concentrate urine, electrolyte abnormalities such as hypokalemia, and
sodium and magnesium wasting. Several factors that modulate
amphotericin B toxicity were described over the last few years, and
different approaches to reducing the renal toxicity of this drug have
recently been identified. Salt supplementation (18, 25) and
encapsulation of amphotericin B into liposomes (19-21) were
shown to reduce significantly the adverse effects of amphotericin B in patients.
Another approach that might contribute significantly to a reduction in
the incidence of amphotericin B toxicity is the time of the day that
the drug is given. In fact, a marked circadian stage dependence of
murine survival time was observed following acute and chronic
administration of amphotericin B (26). Furthermore, we
showed that the renal toxicity of amphotericin B (10 mg/kg of body
weight for 10 days) was higher when the drug was injected into rats at
0700 h than at any other time of day (17). Thus, the
temporal variation in amphotericin B nephrotoxicity could be of
clinical importance because this antifungal agent is usually given to
humans as a once-daily injection (13).
The objective of the present study was to determine the effect of
fasting on the temporal variation in the nephrotoxicity of amphotericin
B. The renal toxicity of amphotericin B was thus investigated in fed
and in fasted rats receiving a single injection of the antifungal agent
at the beginning of their resting period (0700 h) or activity period
(1900 h).
| |
MATERIALS AND METHODS |
Animals and treatment.
Fifty-six female Sprague-Dawley rats
(Charles River Breeding Laboratories Inc., Montréal,
Québec, Canada) that weighed between 184 and 224 g and that
were housed on a 14-h light, 10-h dark cycle (light on at 0600 h)
were used in this study. A week after their arrival, the animals were
divided into two groups of 28 rats each. The first group had free
access to food (Rat Laboratory Chow pellets; Charles River Breeding
Laboratories Inc.) and water throughout the entire experiment. The
second group was fasted for 12 h before and 24 h after the
injection of amphotericin B, but water was available ad libitum. The
length of fasting was set up to minimize stress to the animals. The
first group of rats (n = 7) received a single dose of
amphotericin B (Fungizone; 50 mg/kg given intraperitoneally [i.p.]),
whereas 5% dextrose (1 ml given i.p.) was given to the control
animals. The injection time was 0700 or 1900 h because our
previous study showed that this was the time of maximal (0700 h) and
minimal (1900 h) amphotericin B nephrotoxicity (17). The
single large dose of amphotericin B was used to be able to quantify
renal toxicity by using early and sensitive markers of tubular damage
(urinary enzymes) or late and less sensitive markers (creatinine and
blood urea nitrogen [BUN] levels).
Animals were housed in individual metabolic cages throughout the
experiment, and urine was collected under mineral oil to avoid
evaporation. The urine of each animal was collected over two periods of
24 h (0 to 24 and 48 to 72 h after the injections). The urine
was collected, its volume was noted, and it was centrifuged (1,430 × g) for 15 min. The enzymatic activities of -galactosidase (-GAL) and N-acetyl--D-glucosaminidase
(NAG) were measured in urine. The excretion of these enzymes in urine
are early and sensitive markers of tubular damage.
Immediately before the injection of amphotericin B or dextrose, blood
was collected from the retro-orbital plexus to measure lipid levels in
plasma. The levels of cholesterol, high-density lipoproteins (HDLs),
low-density lipoproteins (LDLs), and triglycerides (TGs) in the plasma
of the fed and fasted rats were determined at the time of the single
injection of amphotericin B since the renal toxicity of amphotericin B
is influenced by serum lipid levels.
All animals were killed by decapitation 72 h after the injection
of amphotericin B or dextrose. At the time of killing, blood
was
collected and centrifuged, and the serum was quickly frozen
at
20°C
to determine serum creatinine and BUN levels. These substances
are late
and less sensitive markers of renal toxicity. A midline
abdominal
incision was made, and both kidneys were removed and
rapidly cut into
two parts. The cortexes of both kidneys were
dissected out, and a piece
of tissue was immediately frozen in
dry ice for determination of
amphotericin B
concentrations.
Biochemical analysis.
The activities of -GAL and NAG were
determined by the method of Maruhn (22). The results are
presented as the percent difference in enzyme activities between the
treated and the time-matched control animals. The baseline levels of
the activities of these enzymes in urine were also determined in fed
and in fasted control rats. Renal function was evaluated by measuring
serum creatinine and BUN levels in the blood collected at the time of
killing. Serum creatinine and BUN levels were determined with a Hitachi 737 apparatus, and the results were presented as the percentage of the
values measured in each time-matched control group. Cholesterol, HDL,
and TG levels in plasma were measured with an RA 500 Tecknicon apparatus, and these results were expressed in millimoles per liter.
Amphotericin B assay.
Samples of cortical tissue were
homogenized in cold distilled water with a Tissue-Tearor RTM (Biospec
Products, Bartlesville, Okla.) and were sonicated (Ultrasonic Processor
W-375; Bionetics Ltd., Montréal, Québec, Canada). The
intracortical accumulation of amphotericin B was determined by the
modified microbiological assay of Bannatyne et al. (2). The
test was performed in triplicate on antibiotic medium 12 (Difco
Laboratories, Detroit, Mich.) with Paecilomyces varioti ATCC
22319 as the indicator organism. The plates were incubated at 37°C
for 18 h. Standards (0.1 to 20 µg/ml) were prepared in blank
cortex homogenized in cold distilled water. The lower limit of
sensitivity of the microbiological assay was 0.53 µg/g of tissue.
Statistical analyses.
Data are presented as means ± standard deviations. The statistical analyses were performed with the
StatView SE + Graphics (1988) program (Abaccus Concepts Inc.,
Berkeley, Calif.). An analysis of variance by a least-squares method
was used to determine the statistical differences between groups. If
the F test indicated a difference within groups
(P < 0.05), group comparisons were carried out with
the Fisher's protected least-significant-difference test, and a
P value of <0.05 was considered statistically significant.
| |
RESULTS |
Urinary enzyme excretion.
Figure
1 presents the percent change in the
level of excretion of NAG and -GAL in urine collected from 0 to
24 h after a single injection of amphotericin B. Fed and fasted
control animals showed similar baseline levels of the activities of
these enzymes in urine. For the fed rats, the excretion of NAG was
significantly higher (P < 0.05) in the urine of rats
treated with amphotericin B at 0700 and 1900 h than in their
time-matched controls. Figure 1A also shows a significant temporal
variation in the toxicity of the drug: amphotericin B treatment
increased the level of NAG excretion by 390% ± 60% at 0700 h
and by 240% ± 90% at 1900 h (P < 0.05). Figure
1A also shows that fasting reduced the level of excretion of NAG
compared with that for the time-matched controls at both times of day
and that this effect was more important at 0700 h than at
1900 h. Fasting abolished the time-dependent variations in NAG
excretion. In urine collected from 48 to 72 h, the NAG activity
was significantly higher in fed and fasted rats treated at 0700 h
than in their time-matched controls and animals treated at 1900 h
(P < 0.05) (data not shown). These data were
predictable since fasted rats had free access to food 24 h after
the single injection of amphotericin B or dextrose.
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FIG. 1.
Twenty-four-hour urinary excretion of NAG (A) and
-GAL (B) (mean ± standard deviation percentage of the control
level of excretion) 0 to 24 h after a single injection of
amphotericin B (50 mg/kg) at 0700 or 1900 h in normally fed and
fasted rats. §, significantly different from time-matched controls
(P < 0.05);  *, statistical difference between
groups under the extremity of the line (P < 0.05).
|
|
The level of excretion of
-GAL in urine measured from 0 to 24 h
after amphotericin B injection is presented in Fig.
1B. Fed
rats
treated at 0700 and 1900 h had significantly higher levels
of
urinary excretion of
-GAL than their time-matched controls
(
P < 0.05), and this effect was greater when the
antifungal agent
was administered at 0700 h than when it was
administered at 1900
h (
P < 0.05). Figure
1B also
illustrates the fact that fasting
reduced the level of
-GAL
excretion at both times of treatment
but that the time-dependent
variations in the nephrotoxicity persisted
in these animals because the
-GAL activities measured at 0700
were still significantly higher
(
P < 0.05) than the activities
found in the urine of
rats injected at 1900 h. No significant
difference in the level of
excretion of
-GAL in urine collected
from 48 to 72 h after
amphotericin B administration was found
(data not
shown).
Renal function.
The effect of amphotericin B on the BUN and
serum creatinine levels in fed and fasted rats 72 h after the
injection is presented in Fig. 2. In
comparison to their time-matched controls, the BUN levels increased
only when fed and fasted rats were treated at 0700 h (Fig. 2A). At
1900 h, injection of the antifungal agent did not induce any
significant change in the BUN levels in either group of rats. Fasting
reduced significantly (P < 0.05) the increase in BUN
levels in animals treated at 0700 h. Figure 2B shows that injection of amphotericin B to fed rats at 0700 h produced serum creatinine levels that were significantly (P < 0.05)
higher than those in the sera of their time-matched controls. A
temporal variation was found in fed rats because the effect of the
antifungal agent on the serum creatinine level was larger at 0700 h than at 1900 h. Fasting abolished the toxicity of the drug on
the kidney because serum creatinine levels remained within the normal
range; no time-dependent variations in serum creatinine levels were
observed in these animals.
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FIG. 2.
BUN (A) and serum creatinine (B) levels (mean ± standard deviation percentage of the control levels) 72 h after a
single injection of amphotericin B (50 mg/kg) at 0700 or 1900 h in
normally fed and fasted rats. §, significantly different from time
matched controls (P < 0.05); *, statistical
difference between groups under the extremity of the line (P < 0.05).
|
|
Intracortical concentration of amphotericin B.
Figure
3 presents the amphotericin B levels in
the renal cortex 72 h after a single amphotericin B injection to
fed and fasted rats at 0700 or 1900 h. Fasting reduced
significantly (P < 0.05) the concentration of
amphotericin B in the renal cortex at both times of the injection.
Furthermore, no significant difference in the accumulation of the drug
in the renal cortex in fed and fasted rats treated at 0700 or 1900 h was found.
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FIG. 3.
Amphotericin B levels (mean ± standard deviation)
in the renal cortex 72 h after a single injection of amphotericin
B (50 mg/kg) at 0700 or 1900 h in normally fed and fasted rats.
The values are expressed as micrograms per gram of tissue. *,
statistical difference between groups under the extremity of the line
(P < 0.05).
|
|
TG, cholesterol, and HDL levels in plasma.
Table
1 presents the HDL, cholesterol, and TG
levels in fed and fasted rat plasma taken a few minutes before
amphotericin B injection. Fasting or time of day did not have any
significant effect on serum HDL levels. However, the cholesterol levels
of fasting rats were significantly (P < 0.05) lower at
1900 h than at 0700 h. Finally, fasting reduced significantly
(P < 0.05) the plasma TG levels at both times of day.
| |
DISCUSSION |
The present study indicates the effects of a short fasting period
on the temporal variations in the nephrotoxicity of amphotericin B. The
excretion of NAG and -GAL in urine and the serum creatinine and BUN
levels were found to be significantly higher in fed animals treated at
0700 h than in fed animals treated at 1900 h. Temporal variations in enzyme excretion persisted in fasted rats, but fasting was associated with a lower level of toxicity of amphotericin B and a
lower level of accumulation of amphotericin B in the renal cortex.
Temporal variations in the nephrotoxicity of amphotericin B have been
reported previously (17, 26). In mice kept on a 12-h light,
12-h dark cycle, Skubitz et al. (26) showed that amphotericin B (35 mg/kg given i.p.) killed 25% of the mice treated early in the resting period (2 h after lights on) and 87% of the mice
treated early in the activity span (2 h after lights off). We
previously studied the nephrotoxicity of amphotericin B produced by
chronic i.p. administration of 10 mg/kg for 10 days using determination of cellular regeneration, BUN and serum creatinine levels, and the
level of accumulation of amphotericin B in the renal cortex (17). In agreement with the present data obtained for fed
rats, our previous study indicates that the highest level of toxicity was obtained when amphotericin B was injected at 0700 h (i.e., at
the beginning of the resting period) compared with that when amphotericin B was injected at some other time of day.
The mechanisms of the temporal variation in the nephrotoxicity of
amphotericin B are still unknown. In agreement with our previous work
(17), a first hypothesis could be that the highest level of
toxicity of the antifungal agent observed at 0700 h is due to
temporal changes in the level of accumulation of drug in the kidney and
in its pharmacokinetics. Unfortunately, these data could not be
reproduced in the present study. This discrepancy could be explained by
methodological differences because the effect of chronic administration
of the amphotericin B was studied in our previous work (17),
while determination of the effect of fasting forced us to use a single
acutely administered large dose in the present work. Could the
time-dependent variations in the nephrotoxicity of amphotericin B be
explained by temporal changes in the pharmacokinetics of the drug? To
date, no data support this aspect of the hypothesis. However, the
temporal changes in pharmacokinetics may not explain the data because
amphotericin B has a long elimination half-life in human serum (15 days; only 3% of the total dose is excreted by the kidneys)
(1) and in rats (16 to 18 h) (14). In
addition, no data in the literature describe the effect of fasting on
the pharmacokinetics of amphotericin B in serum and tissue. Thus,
further studies are needed to confirm or refute this first working hypothesis.
Another possibility could be that the effect of diet on amphotericin B
is due to an interaction between the antifungal agent and cholesterol,
proteins, or lipoproteins in the blood (5, 9). Studies done
with experimental animals suggested that the renal toxicity of
amphotericin B is either increased when LDL-associated amphotericin B
was given to hypercholesterolemic rabbits (15) or decreased
in the presence of increased levels of TGs in serum (8, 27)
or when the interaction between amphotericin B-LDL is inhibited
(3). Studies done with humans suggested that low cholesterol
levels in serum are associated with a lower level of renal toxicity of
amphotericin B (7, 24) but that a higher incidence of
toxicity was observed in patients with high serum LDL-cholesterol
levels (30, 32). Experiments done in cell culture suggest
that an increase in the level of association of amphotericin B with LDL
enhanced the toxicity of amphotericin B to kidney cells (31,
32) since the cellular uptake of amphotericin B seems to be
mediated through the LDL receptors (16).
Our study shows significant differences in the renal toxicity of
amphotericin B in fed animals injected at 0700 and 1900 h in the
presence of similar levels of TGs and cholesterol in serum. However,
these differences were significantly attenuated by fasting, which
induced significantly lower levels of TGs in serum but similar levels
of cholesterol. In other words, the protective effect of fasting seems
to correlate with the low serum TG levels. By contrast, Chavanet et al.
(8) found that serum TG levels correlated significantly with
the 50% lethal dose of amphotericin B in mice. It is thus clear that
the relationship between amphotericin B nephrotoxicity and the levels
of TGs in serum as well as the levels of other serum components should
be investigated further.
A last hypothesis could be that the susceptibility of the kidney to
amphotericin B administration varied as a function of time of day
because of temporal changes in the level of binding of amphotericin B
with its receptor sites. Binding would be increased when the animals
are eating, and this would explain why the toxicity was the greatest at
the end of the activity period (i.e., at 0700 h). Fasting would
reduce the level of binding to the receptor sites, and this would
explain why the nephrotoxicity was least at the end of the resting
period because rodents are not eating much in their sleeping period.
Further research at the receptor level is needed to prove or disprove
this working hypothesis.
| |
ACKNOWLEDGMENTS |
This study was supported by the Fonds pour la Formation de
Chercheurs et l'Aide à la Recherche. M. LeBrun is the recipient of a studentship from the Fonds pour la Formation de Chercheurs et
l'Aide à la Recherche.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Centre de
Recherche en Infectiologie, Centre de Recherche du CHUL, 2705 Boul.
Laurier, Ste-Foy, Québec, Canada G1V 4G2. Phone: (418) 654-2705. Fax: (418) 654-2715. E-mail:
denis.beauchamp{at}crchul.ulaval.ca.
| |
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Antimicrobial Agents and Chemotherapy, March 1999, p. 520-524, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
