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Nephrotoxicity of amphotericin B is attenuated by solubilizing with lipid emulsion
1Laboratório de Pesquisa Básica da Disciplina de Nefrologia da Faculdade de Medicina da Universidade de São Paulo, Brazil.
Abstract:
Nephrotoxicity is the major adverse effect of conventional amphotericin B (AMB/D), often limiting administration of full dosage. The new liposomal amphotericin B seems to be less toxic. The new liposomal amphotericin B seems to be less toxic. In this study, it is proposed that solubilizing the standard AMB/D preparation with 10% lipid emulsion will attenuate nephrotoxicity. Rats were injected with either AMB/D (Fungizone), AMB, AMB/D plus lipid emulsion (AMB/D/LE), or sodium deoxycholate (D). Renal function studies were performed on day 5. To assess a direct tubular toxic effect, isolated rat proximal tubule suspensions and inner medullary collecting duct cells in culture were exposed to AMB/D, AMB, AMB/D/LE, liposomal amphotericin B, and D for 60 min in normoxia. Lactate dehydrogenase (LDH) release was assessed as an index of cell injury. Creatinine clearance (ml/min per 100 g) averaged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.001 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rats, and 0.78 +/- 0.03 in AMB/LE rats. Renal blood flow (ml/min per 100 g) was 3.45 +/- 0.31 in control, 1.29 +/- 0.28 in AMB, 1.42 +/- 0.23 in AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The fractional excretion of potassium (%) was 27.3 +/- 1.18 in control rats, 61.6 +/- 7.00 in AMB/D rats, 58.4 +/- 15.32 in AMB rats, and 37.9 +/- 2.06 in AMB/D/LE rats. LDH release (%) in proximal tubules incubated with AMB/D and D was 43.6 +/- 3.39 and 58.6 +/- 4.20, respectively. Addition of lipid emulsion decreased LDH release: 21.6 +/- 1.22 for AMB/D/LE and 26.4 +/- 3.03 for deoxycholate plus lipid emulsion. AMB did not demonstrate any toxic effect in proximal tubule suspensions. D was not toxic to inner medullary collecting duct cells at 0.16 mg/ml, whereas D at a higher dose and AMB induced a significant LDH release. Addition of lipid emulsion did not affect the antifungal activity as assessed by the Etest method. In conclusion, an alternative way of administering standard AMB with reduced nephrotoxicity is proposed.
Insights
Solubilizing conventional amphotericin B (AMB/D) with lipid emulsion reduces its toxicity to rat kidneys and kidney cells. This method preserves antifungal activity, offering a safer alternative for AMB/D administration.
Area of Science:
- Pharmacology
- Nephrology
- Mycology
Background:
- Conventional amphotericin B (AMB/D) is effective against fungal infections but its use is limited by significant nephrotoxicity.
- Liposomal formulations of amphotericin B have been developed to reduce toxicity, but novel approaches are still needed.
Purpose of the Study:
- To investigate whether solubilizing standard AMB/D with a 10% lipid emulsion can attenuate its nephrotoxicity.
- To assess the direct tubular toxic effects of AMB/D and its lipid emulsion formulation on renal cells.
Main Methods:
- Rats were administered AMB/D, AMB/D with lipid emulsion (AMB/D/LE), or other controls, and renal function was assessed.
- Isolated rat proximal tubule suspensions and inner medullary collecting duct cells were exposed to different AMB formulations to measure cell injury via lactate dehydrogenase (LDH) release.
- Antifungal activity was evaluated using the Etest method.
Main Results:
- AMB/D/LE administration in rats resulted in creatinine clearance and renal blood flow comparable to control groups, unlike AMB/D alone.
- Lipid emulsion significantly reduced LDH release in both proximal tubule cells and inner medullary collecting duct cells exposed to AMB/D.
- The lipid emulsion did not compromise the antifungal efficacy of amphotericin B.
Conclusions:
- Solubilizing standard amphotericin B with lipid emulsion is a promising strategy to reduce its nephrotoxicity.
- This formulation offers a potential alternative for administering amphotericin B with an improved safety profile.
- Further studies are warranted to explore this novel delivery method for antifungal therapy.