Effect of antipyrine and phenobarbital on renal gamma-glutamyltransferase excretion in human urine.

Serum gamma-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of gamma-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and gamma-glutamyltransferase, on the urinary excretion of renal gamma-glutamyltransferase. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum gamma-glutamyltransferase, and the urinary excretion of renal gamma-glutamyltransferase, whereas urinary beta-N-acetylglucosaminidase, beta-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary gamma-glutamyltransferase or both enzymes and antipyrine elimination. Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary gamma-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary gamma-glutamyltransferase excretion. However, the increase in urinary gamma-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.

Amphotericin B nephrotoxicity in humans decreased by salt repletion.

A major limitation in the use of amphotericin B is its potential to cause nephrotoxicity. In animals, increased dietary sodium reduces renal toxicity. Experience with five patients in whom impaired renal function developed early during amphotericin B therapy is reported. In four of the patients, there was evidence of sodium depletion due to low sodium intake, diuretic administration, or vomiting. In all five patients, sodium loading was associated with improved renal function, which permitted amphotericin B therapy to be continued in fully effective doses to the completion of elective courses of treatment without evidence of residual impaired renal function. These observations are consistent with the hypothesis that intrarenal regulatory mechanisms contribute to changes in renal function due to amphotericin B therapy.

Effect of aminophylline on cisplatin nephrotoxicity in the rat.

1. The effect of the methylxanthine aminophylline on cisplatin (5 mg kg-1 i.v.)-induced acute renal failure was investigated in the rat. Renal function was measured 5 days after cisplatin administration. 2. Cisplatin caused a polyuric acute renal failure. The creatinine clearance was significantly reduced. 3. Aminophylline (24 mg kg-1 12h-1) ameliorated the cisplatin nephrotoxicity when administered during the maintenance phase of acute tubular necrosis. However, it had no effect when only administered prophylactically before the cisplatin application. 4. Enprofylline (20 mg kg-1 4h-1 with dose adjustment), a methylxanthine lacking adenosine receptor antagonism in comparison to aminophylline, had no protective effect on cisplatin nephrotoxicity. 5. Adenosine is a renal vasoconstrictor and decreases glomerular filtration rate. Endogenous adenosine in the kidney is formed by degradation of ATP and is thought to be involved in various forms of acute renal failure. The results suggest that adenosine may be involved in the haemodynamic changes in the kidney induced by cisplatin.

Influences of Ginkgo biloba on cyclosporin A induced lipid peroxidation in human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine.

The in vitro effect of cyclosporin A (CsA) on lipid peroxidation in human liver microsomes was investigated, and efforts were made to prevent the resulting toxic effect of CsA. Microsomes were prepared from human liver resection material and incubated with CsA (0, 10, 30, 100, 300, 1000 micrograms/mL) for one hour (pH 7.4, 37 degrees, 95% O2, 5% CO2). Subsequently the resulting concentrations of malondialdehyde equivalents (MDA) were determined, a breakdown product of lipid peroxidation. Furthermore the duration of incubation was varied (0, 15, 30, 60, 90 min) using a CsA concentration of 300 micrograms/mL. CsA was shown to stimulate MDA-formation to up to 10-fold of the control value in both a time and concentration dependent manner. The dosage dependent experiment stated above was repeated, adding alpha-tocopherol (vitamin E, 1 mM), reduced glutathione (GSH, 1 mM), N-acetylcysteine (0.1, 0.3, 1, 3 mM), and Ginkgo biloba extract (Gbe, 15, 50, 150 micrograms/mL), respectively, to the medium of incubation. Vitamin E, a potent radical scavenger, proved to inhibit lipid peroxidation almost totally. Both GSH and N-acetylcysteine were also able to prevent lipid peroxidation, suggesting that the antioxidant effect of GSH might be caused by its thiol group and does not depend on the integrity of the whole molecule. Gbe inhibited CsA induced lipid peroxidation in a concentration dependent manner. This effect of Gbe was diminished yet not totally abolished when FeCl3 was added to the medium of incubation, whereas N-acetylcysteine even slightly enhanced CsA stimulated lipid peroxidation in the presence of iron. These results suggest that Gbe might be able to prevent radical mediated damage to human membranes caused by CsA.

Attenuation of cisplatinum-induced nephrotoxicity in the rat by high salt diet, furosemide and acetazolamide.

The influence of variations in sodium chloride diet, furosemide and acetazolamide on nephrotoxicity induced by cisplatinum have been investigated in the rat by measuring serum creatinine concentrations 5 days after cisplatinum (5 mg/kg, ip) administration. Sodium chloride depletion enhanced, while sodium chloride loading minimized changes in renal function. Increases in urine flow rate following a dextrose water load failed to alter the nephrotoxic response. Both furosemide and acetazolamide, given 30 min before cisplatinum, attenuated the nephrotoxic response. In contrast, neither sodium chloride loading, furosemide, nor acetazolamide influenced the change in renal function when given 30 min after cisplatinum. These observations indicate that renal damage due to cisplatinum can be modified by alterations in dietary salt and by diuretics and that the extent of ultimate renal damage is dependent on factors occurring immediately after cisplatinum administration.

Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat.

Administration of the antifungal agent amphotericin B causes a pronounced reduction in renal blood flow (RBF). Since amphotericin B induced renal vasoconstriction may contribute to the clinical nephrotoxicity of this drug, the purpose of these studies was to investigate the mechanism of amphotericin B induced renal vasoconstriction. To determine if the vascular response to amphotericin B is linked to the intrarenal release of either adenosine or angiotensin II, the effects of aminophylline (5 mumol/kg/min for 10 min followed by 0.5 mumol/kg/min) and saralasin (6 micrograms/min) on the renal vascular response produced by two 10 min intravenous amphotericin B (0.35 mg/kg) infusions were examined. In the control group, amphotericin B decreased RBF 1.7 ml/min (22%, P less than 0.01) and 3.5 ml/min (44%, P less than 0.001) during the 1st and 2nd amphotericin B infusions, respectively. In animals pretreated with aminophylline the decrease in RBF produced by amphotericin B was only 0.4 ml/min (5.5%; N.S.) and 1.3 ml/min (15%, P less than 0.05) during the 1st and 2nd amphotericin B infusions, respectively. In contrast, neither saralasin nor the direct vasodilator sodium nitroprusside (0.4-2 micrograms/min) influenced the renal vascular response to amphotericin B. These data suggest that the renal vascular response to amphotericin B is not linked to the formation of angiotensin II, but rather might be mediated by increases in renal adenosine levels.

Effect of flucytosine on renal function in the rat.

Flucytosine (5-fluorocytosine), a potent antimycotic drug against various systemic infections such as candidosis, aspergillosis and cryptococcosis, is extensively excreted by the kidneys, yet its possible role in renal function is not known. In the present study flucytosine, administered intravenously, increased significantly renal blood flow (RBF) by 26% from 5.06 +/- 0.9 ml/min/kidney. The renal vasodilation was combined with an elevation of creatinine clearance of 140% from a baseline value of 0.23 +/- 0.11 ml/min/kidney. This improvement in renal function was accompanied by an increase in filtration fraction, urine volume and potassium excretion. In comparison, rats administered an equal amount of 5% glucose only showed no changes in the values of these parameters.

Hypokalemic rhabdomyolysis with myoglobinuria due to licorice ingestion and diuretic treatment.

A 54-year-old man was admitted to hospital with acute rhabdomyolysis and myoglobinuria due to hypokalemia. The hypokalemia was due to chronic licorice ingestion and diuretic treatment. The myoglobinemia led to a glomerulopathy and tubulopathy. There was, however, no clinical evidence of acute renal failure (ARF). We propose that the volume expansion caused by the steroid-like actions of licorice might have prevented the development of an ARF.

Effect of 5-fluorocytosine and 5-fluorouracil on human and rat hepatic cytochrome P 450.

Hepatotoxicity is a well-known side effect of the antifungal drug 5-fluorocytosine. The underlying mechanisms of this toxicity are unknown. The present in vitro study was, therefore, designed to assess the influence of 5-fluorocytosine and 5-fluorouracil on the hepatic cytochrome P 450 concentration in human and rat liver microsomes. Incubation of human or rat hepatic microsomes for 1 h with 5-fluorocytosine up to 500 micrograms/ml or with 5-fluorouracil up to 200 micrograms/ml did not influence the cytochrome P 450 concentration. In comparison the amount of cytochrome P 450 in human liver, however, was lower than in rat liver microsomes and a more interindividual variation was observed.

Amphotericin B and sodium deoxycholate induced impairment of renal p-aminohippurate accumulation (PAH) and effect on lipid peroxidation in the rat kidney.

The influence of amphotericin B on PAH transport as well as on lipid peroxidation in rat renal cortical slices was studied in vitro and ex vivo. In vitro, renal cortical slices were incubated with different amphotericin B (AmB) concentrations (2-60 micrograms/mL) or with the corresponding vehicle concentrations of sodium deoxycholate (NaDo) (1.64-49.2 micrograms/mL) and time dependently (15-30-60 min) with 30 micrograms/mL AmB or 24.6 micrograms/mL NaDo. Ex vivo, PAH transport of renal cortical slices was investigated following a 3-day intravenous AmB administration with 3 mg/kg per day or 2.46 mg/kg/day NaDo, respectively. In vitro AmB as well as NaDo decreased PAH transport dose and time dependently. At the highest AmB concentration of 60 micrograms/mL, PAH uptake decreased to 17.6%. The corresponding NaDo concentration (49.2 micrograms/mL) decreased PAH uptake to 33.3%. Time dependently AmB decreased PAH uptake to 25% after 60 min. NaDo caused a decrease to 69%. Administration of AmB for 3 days resulted in a PAH decline to 81%; NaDO decreased PAH uptake to 77%. In vitro as well as in vivo, AmB or its vehicle did not induce lipid peroxidation in renal cortical tissue. In summary, the results show that AmB and its vehicle, NaDo, decrease PAH uptake by renal cortical cells, reflecting a direct effect of AmB on tubular function. The impairment of the PAH transport is not due to enhanced lipid peroxidation.

[Endogenous candida endophthalmitis in a drug dependent patient: intravenous therapy with liposome encapsulated amphotericin B]. / Endogene Candida-Endophthalmitis bei einem Drogenabhängigen: intravenöse Therapie mit liposomal verkapseltem Amphotericin B.

We report this exemplary case of a drug addict with candida endophthalmitis where we used the new form of amphotericin B, encapsulated in liposomes. We were able to reconfirm the reduced number of side effects and the minimized nephrotoxicity reported by authors of other specialties. In our patient, a reduction or elimination of the yeast was probably achieved, nevertheless, he developed a traction retinal detachment. In future cases of fungal endophthalmitis, we recommend liposomal amphotericin B in higher doses.

Cyclosporin-A-induced lipid peroxidation in human liver microsomes and its influence on cytochrome P-450.

The present in vitro study using human liver tissue was performed to investigate the effect of cyclosporin A on lipid peroxidation and cytochrome P-450 concentration in isolated liver microsomes. Incubations were either carried out with cyclosporin A concentrations of 10, 30, 100 and 300 micrograms ml-1 for 1 h or for different time periods (15, 30, 60 and 90 min) with cyclosporin A 300 micrograms ml-1. Lipid peroxidation was monitored measuring the amount of malondialdehyde. In additional experiments the effect of reduced and oxidized glutathione (1 mM) on cyclosporin-A-induced lipid peroxidation in human liver microsomes was studied. Cyclosporin A caused a significant dose and time-dependent increase of the lipid peroxidation product malondialdehyde. At the highest cyclosporin A concentration (300 micrograms ml-1) malondialdehyde production increased 5-fold in comparison to corresponding control values. Incubations for different time periods resulted in a 5-fold net increase of malondialdehyde formation after 90 min. In the presence of reduced glutathione, cyclosporin-A-induced lipid peroxidation was significantly inhibited. Furthermore, cyclosporin-A-induced microsomal lipid peroxidation was accompanied by a significant dose-dependent decline of the microsomal cytochrome P-450 content. At a cyclosporin A concentration of 300 micrograms ml-1, cytochrome P-450 content was decreased to 49% in comparison to control values. In the presence of reduced glutathione, cyclosporin A decreased the cytochrome P-450 concentration only to 79% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of chronic theophylline administration on amphotericin B nephrotoxicity in rats.

The effect of chronic theophylline administration on amphotericin B nephrotoxicity was investigated in rats. A 7-day treatment of amphotericin B (5 mg/kg/day i.p.) significantly reduced the glomerular filtration rate (GFR) measured as inuline clearance and creatinine clearance (0.74 +/- 0.29 and 0.16 +/- 0.04 ml/min, respectively) in comparison to vehicle-treated rats (2.04 +/- 0.23 and 1.29 +/- 0.19 ml/min, respectively). The reduced GFR led to evaluations in serum creatinine and BUN concentrations (0.94 +/- 0.09 and 78 +/- 11 mg/dl) in comparison to their own values before treatment (0.45 +/- 0.11 and 19 +/- 3 mg/dl). In addition amphotericin B induced an increase in sodium and a decrease in potassium excretion, the fractional sodium excretion was elevated 50-fold. The methylxanthine, theophylline, had a beneficial effect on the outcome of amphotericin-B-induced renal failure. The inuline clearance was 1.17 +/- 0.04 ml/min, the creatinine clearance 0.43 +/- 0.03 ml/min, the serum creatinine concentration 0.76 +/- 0.05 mg/dl and the BUN concentration 40 +/- 6 mg/dl. Theophylline had no effect on total sodium excretion and potassium excretion. The fractional sodium excretion, however, improved significantly. Theophylline as well as sodium deoxycholate, the detergent of amphotericin B, given alone had no effect on renal hemodynamics measured after 7 days.

Antipyrine elimination in patients with alcoholic and non-alcoholic cirrhosis.

The metabolism of antipyrine to each of its three major metabolites 4-hydroxy-, 3-methylhydroxy- and norantipyrine has previously been demonstrated to be differentially affected in alcoholic cirrhosis. This study compared the metabolism of antipyrine to its metabolites in 30 patients with alcoholic cirrhosis to 15 patients with non-alcoholic cirrhosis and 20 healthy controls. Both groups of cirrhotic patients were comparable with respect to their disease stage, as assessed by the Child-Pugh classification. Compared to controls, patients with alcoholic and non-alcoholic cirrhosis showed a comparable significant reduction in antipyrine clearance and increase in antipyrine half-life. The reduction in antipyrine clearance was due to a reduction in the formation rate of all three antipyrine metabolites in both alcoholic and non-alcoholic cirrhotics. In both groups, the formation rate of norantipyrine was reduced to a greater extent than of 3-methylhydroxy- and 4-hydroxyantipyrine. No significant differences in the parameters of antipyrine elimination, however, were observed between patients with alcoholic and non-alcoholic cirrhosis. Parameters of antipyrine elimination correlated significantly to the Child-Pugh score and single laboratory parameters, however, the correlation coefficients were generally low (< 0.56). The present results suggest that the P450 enzymes involved in antipyrine metabolism are differentially affected in cirrhosis, but there appear to be no differences in the activity of the enzymes between alcoholic and non-alcoholic cirrhosis. Antipyrine metabolism, therefore, depends on the severity rather than the etiology of liver disease and may serve as a measure of hepatic function irrespective of the cause of liver disease.

Comparison of the effects of liposomal amphotericin B and conventional amphotericin B on propafenone metabolism and hepatic cytochrome P-450 in rats.

The effects of conventional amphotericin B (AmB) dissolved in sodium deoxycholate on microsomal cytochrome P-450 concentrations and propafenone metabolism to 5-hydroxy-propafenone and N-desalkyl-propafenone were compared with those of liposomal AMB (Li-AMB) in rats. AmB (3 mg/kg/day, intravenously [i.v.]) given for 4 days caused a significant decrease in the concentration of hepatic microsomal cytochrome P-450 (0.43 +/- 0.06 nmol/mg versus 0.62 +/- 0. 05 nmol/mg for the control [P < 0.05]). Following the application of Li-AMB (15 mg/kg/day, i.v.), hepatic microsomal cytochrome P-450 concentrations were unchanged at 0.64 +/- 0.08 nmol/mg. AmB decreased ex vivo propafenone metabolism to 5-hydroxy-propafenone and N-desalkyl-propafenone significantly. Sodium deoxycholate (the vehicle of AmB) by itself induced a significant decline of 5-hydroxy-propafenone and N-desalkyl-propafenone production, while microsomal cytochrome P-450 concentrations remained unchanged. In contrast, Li-AMB did not change the levels of production of 5-hydroxy-propafenone or of N-desalkyl-propafenone at either substrate concentration tested (50 micromol and 200 micromol). Microsomal AmB concentrations were significantly higher following Li-AMB application (21.1 +/- 6.2 microg/g versus 3.7 +/- 1.4 microg/g for AmB [P < 0.05]). We conclude that Li-AMB, in contrast to AmB, decreases neither hepatic microsomal cytochrome P-450 nor hepatic propafenone metabolism in rats ex vivo. Sodium deoxycholate alone decreases propafenone metabolism in a similar way to AmB, suggesting that it participates in AmB-induced disturbance of hepatic metabolic function.

Liposomal amphotericin B (AmBisome) application and hepatic microsomal enzyme function in the rat.

In the present study we investigated the influence of AmBisome, a lyophilized liposomal amphotericin B formulation on various hepatic cytochrome P450-dependent mixed function oxidases, antipyrine clearance and hepatic glucose-6-phosphatase activity in rats. Animals were treated intravenously for 6 days with AmBisome (15 mg kg-1 body weight). Subsequently, the enzyme activities and cytochrome P450 concentrations were measured ex vivo in hepatic microsomes. Following AmBisome the activity of the microsomal ethoxycoumarin-O-deethylase increased significantly from 333 +/- 77 pmol mg-1 to 459 +/- 125 pmol mg-1, whereas benzpyrenhydroxylase and glucose-6-phosphatase did not change compared with the controls. Accordingly, antipyrine clearance was not affected by AmBisome treatment. Microsomal cytochrome P450 concentrations as well as total microsomal protein concentrations were not changed following treatment with AmBisome and it did not affect either serum levels of liver transaminases or bilirubin. The results show that the application of a high AmBisome dose had no adverse effects on a variety of microsomal hepatic enzymes and the antipyrine clearance in rats. Thus, it seems likely that AmBisome does not seriously impair metabolic liver function.

Amphotericin B and liver function.

Amphotericin B is well established as a highly efficacious agent against systemic fungal infections in humans. The therapeutic potential of amphotericin B is limited due to its side effects. Although in clinical use for more than 35 years, impairment of liver function is not considered to be a typical adverse effect of amphotericin B. Experimental data suggest that the drug may interfere with the hepatic cytochrome P450 and may thus influence the metabolic capacity of the liver. A confirmation of such a finding in patients treated with amphotericin B would be of value. The incidence of severe acute or subacute hepatotoxicity in response to amphotericin B is very low. Frequently, in critically ill patients, it is not always clear whether liver abnormalities are caused by an antifungal agent or whether they are due to the critical condition of these patients. Nevertheless, there are experimental data suggesting that amphotericin B may influence the metabolic capacity of the liver. Accordingly, drug interactions during prolonged amphotericin B treatment seem possible. Careful monitoring of liver function in those patients receiving amphotericin B in combination with other drugs, which undergo hepatic metabolism or are potentially hepatotoxic, is recommended. In this review, the current understanding and knowledge of the clinical significance, detection, and possible pathogenesis of amphotericin-B-induced liver damage are presented. With respect to the current experimental data, the influence of the drug on the hepatic microsomal cytochrome P450 are also presented and discussed, as is the impact of several clinical studies using different amphotericin B formulas in humans.

Long-term effects of acetazolamide and sodium chloride loading on cisplatin nephrotoxicity in the rat.

The protective effect of acetazolamide or sodium chloride loading on cisplatin nephrotoxicity was investigated in rats. After a single dose of cisplatin (5 mg kg-1 i.p.) kidney function was studied after 5, 28 and 84 days. Acetazolamide (75 mg kg-1 i.p.) was administered as a single dose prior (30 min) to the cisplatin injection. By the time of cisplatin administration, the rats were sodium depleted except the sodium-loaded group. Five days after the cisplatin administration all rats received a regular rat chow for the rest of the experiment. Cisplatin alone caused renal failure that could be observed for up to 12 weeks (ClCr 0.32 +/- 0.13 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with polyuria (UVol 41.2 +/- 4.5 vs. 18.4 +/- 4.6 ml 24 h-1). Pretreatment with acetazolamide was the most protective manoeuvre tested. Five days after cisplatin, kidney function was significantly better than in rats treated with cisplatin alone (ClCr 0.21 +/- 0.06 vs. 0.03 +/- 0.01 ml min-1 x 100 g BW-1), after 28 days the only sign of nephrotoxicity was polyuria (UVol 28.9 +/- 3.7 vs. 19.0 +/- 2.6 ml 24 h-1) after 84 days no differences could be observed at all. Sodium chloride loading was less protective on cisplatin nephrotoxicity. Impaired renal function could still be observed after 12 weeks (ClCr 0.41 +/- 0.05 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with no difference in comparison with the rats treated with cisplatin alone. However, since 12 rats died in the group having received cisplatin alone and only one rat in the high-salt group, sodium chloride loading is regarded as being advantageous over sodium depletion on cisplatin nephrotoxicity.

Intrarenal hypertonic saline infusions in dogs with thoracic caval constriction.

Intrarenal artery infusions of hypertonic saline can activate tubuloglomerular feedback (TGF), decreasing renal blood flow (RBF) and glomerular filtration rate (GFR). The response to infusion of hypertonic saline is enhanced by salt depletion and attenuated by salt loading, but has not previously been investigated in pathophysiological states where expanded extracellular fluid volume due to salt retention is associated with avid, renal sodium reabsorption. The renal response following intrarenal infusions of hypertonic saline was investigated in five control dogs and eleven dogs with partial constriction of the thoracic portion of their inferior vena cava, which resulted in salt retention and the formation of ascites. Intrarenal infusion of hypertonic saline induced significant reductions in RBF and GFR in both control and caval constricted dogs. The extent of these reductions were positively correlated with baseline renal function. An intravenous infusion of 50 ml/kg of 0.9% sodium chloride, which abolished the vasoconstrictor response in normal dogs, failed to abolish the decrease in RBF and GFR in response to intrarenal hypertonic saline infusion in dogs with ascites which had an initial vasoconstrictor response. We conclude that the potential for TGF is preserved in early stages of caval constriction syndrome in dogs, but that this potential activity decreases when basal renal function decreases.

Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats.

The combination of intravenous flucytosine (FC) in 0.9% saline (NaCl) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 +/- 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mg/kg/12 h) in 0.9% saline (15 ml/kg/12 h); group 3, 0.9% saline (15 ml/kg/12 h); and group 4, FC (150 mg/kg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in serum creatinine concentration (P of < 0.05). Groups 2, 3, and 4 sustained significantly less nephrotoxicity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of < 0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of < or = 0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results of this study suggest that FC has a small but significant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.