Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats

Abstract

The aim of the present study was to assess whether amphotericin B (AmB)-Myrj 59, AmB-polyoxyethyleneglycol 24 cholesterol (PC), and AmB-Synperonic A50 (SA50) were less nephrotoxic than AmB-deoxycholate (DC). Rats were treated with the different AmB formulations (10 mg/kg of body weight) intraperitoneally or with the surfactants alone. A group of control rats receiving the vehicle was also examined. After 6 days of daily intraperitoneal inijections of AmB-DC, decreased body weight and glomerular filtration rate as well as increased degree of diuresis, uremia, microalbuminuria, and N-acetyl-O-D-glucosaminidase excretion in urine were noted. Urinary excretion of potassium and sodium was also decreased in AmB-DC-treated rats. Most of these effects were more pronounced with AmB-PC and AmB-SA50. In contrast, AmB-Myrj 59 was less nephrotoxic than AmB-DC. Indeed, after 6 days of treatment with AmB-Myrj 59, the natriuria, kaliuria, albuminuria, and glomerular filtration rates were unchanged compared with those of controls. Moreover, the body weight loss and uremia increase of the rats treated by AmB-Myrj 59 were less than those of the rats treated with the commercial preparation. Among the surfactants, only PC was toxic for the rats. The intrinsic toxicity of PC and the higher systemic exposure to AmB could contribute to increased toxicities ofAmB-PC and AmB-SA50, respectively. AmB-Myrj 59 was less nephrotoxic than AmB-DC at equivalent areas under the plasma concentration-time curves. These preliminary results suggest that this formulation could be a good alternative to the commercial product.Amphotericin B (AmB) is a polyene antibiotic which is widely used in the treatment of systemic mycoses despite two major disadvantages. First, AmB is poorly water soluble, and the commercial preparation (Fungizone) consists of a colloidal solubilization of the drug in a micellar solution of deoxycholate (AmB-DC). Second, toxicity of the polyene limits its clinical use. Particularly, the chronic nephrotoxicity which affects up to 80% of the patients treated with AmB-DC (13) can sometimes lead the clinician to lower the dose or to prematurely discontinue therapy (8,46). Usually, renal function returns to normal upon withdrawal of therapy (5), although sometimes permanent damage is sustained (49).The mechanism of this nephrotoxicity is not yet well understood. It is characterized by an increase in the tubular permeability, leading to the inability of the kidneys to concentrate the urine (5, 13, 16, 38); to distal tubular acidosis (11,16,20,38); and to potassium, sodium, and magnesium wasting (4,11,16,37,38). This effect is probably due to the direct interaction of AmB with the cell membrane (12, 15) and could be related to the ability of the antibiotic to alter the membrane permeability (1). AmB also induces a decrease in the glomerular filtration rate and in the renal blood flow (11,13,14,16,39 lytic acitivity of AmB by decreasing its affinity for the cellular membranes (29a). However, we previously showed that cholesterol is not nece...

Formulation and Evaluation of Microemulsion Based Delivery System for Amphotericin B

“…However it was less effective than alternate amphotericin B formulations in bringing about a reduction in toxicity. Similar observation of decrease in hemolytic potential with no significant change in the LD 50 value has been reported for amphotericin B-PEG 100 stearate complex (12), and certain liposomal preparations of the drug (20). On the other hand a great deal of reduction in toxicity is reported with other lipid based amphotericin B formulations such as Ambisome \ and Abelcet \ .…”

“…Amphotericin B preferably exists in monomeric form when complexed with Myrj 59 \ (polyethylene glycol 100 stearate) as reported by Tasset et al (12). However in the present study amphotericin B is found to be in aggregated form despite complexation with Mys 40 \ (polyethylene glycol 40 stearate).…”

“…This could be attributed to complexation of drug with PEG-derivatives. Tasset et al (12) have reported a reduction in hemolytic activity of drug on complexation with PEG 100 stearate also brought about by co-evaporation from dimethylformamide, attributing the decrease to the protection offered to the cells by PEG 100 stearate. The authors have also cited the increased selectivity of the complexed amphotericin B for ergosterol to be another reason for decrease in hemolytic potential.…”

“…Reports of good solubility of amphotericin B in glyceryl mono-oleate (Peceol \ ) prompted inclusion of this oil in the study (10) Solubility in Peceol \ determined at 30±2°C was found to be 0.312 mg /ml. Further, amphotericin B is reported to form water soluble complexes with various PEG-derivatives including PEG 24 cholesterol, and PEG 100 stearate (11,12), and Pluronic F 127 & L 92 (13). Hence two PEG based surfactants were evaluated in the present study, polyethylene glycol 40 stearate (Mys 40 \ ) and polyethylene glycol 15 hydroxy stearate (Solutol HS 15 \ ), and were also found to form water soluble complexes with amphotericin B on coevaporation from dimethyl formamide.…”

A Chemically Modified Tetracycline (CMT-3) Is a New Antifungal Agent

“…For example, recommended doses of AMB may produce adverse effects, such as fever, nausea, hypokalemia, nephrotoxicity, hepatotoxicity, leukocytopenia, thrombocytopenia, anemia, chills, and even death (15,16,26). It has also been reported that prolonged use of AMB can induce disseminated candidiasis in humans (4).…”