title: Nephrotoxicity of amphotericin B is attenuated by solubilizing with lipid emulsion.
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.
authors.affiliation: Laboratório de Pesquisa Básica da Disciplina de Nefrologia da Faculdade de Medicina da Universidade de São Paulo, Brazil.
authors.forename: E L
authors.initials: EL
authors.lastname: Dórea
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: I
authors.initials: I
authors.lastname: De Castro
authors.forename: S B
authors.initials: SB
authors.lastname: Campos
authors.forename: M
authors.initials: M
authors.lastname: Ori
authors.forename: E M
authors.initials: EM
authors.lastname: Vaccari
authors.forename: C da S
authors.initials: Cda S
authors.lastname: Lacaz
authors.forename: A C
authors.initials: AC
authors.lastname: Seguro
mesh_terms: D000666:Amphotericin B / Q000506:poisoning*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000506:poisoning*; D002478:Cells, Cultured; D004655:Emulsions; D007668:Kidney / Q000187:drug effects* / Q000382:microbiology / Q000503:physiopathology; D007679:Kidney Medulla; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D000900:Anti-Bacterial Agents; D004655:Emulsions; D008055:Lipids; D000666:Amphotericin B; D007770:L-Lactate Dehydrogenase