Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits.
To investigate the protective effect of liposomes on acute amphotericin B (AMB) renal toxicity, we compared in rabbits the acute toxicity of 4 mg/kg of free-AMB and 4 or 10 mg/kg of liposomal AMB (L-AMB) during 90 min after antibiotic infusion. Free-AMB exhibited immediate nephrotoxicity with a 44% decrease of the glomerular filtration rate and alteration of tubular cell membrane permeability expressed as increases in urinary pH (6.5 vs. 4.7), potassium fractional excretion (95% vs. 30%) and sodium fractional excretion (26% vs. 4%). Urinary excretion of the lysosomal enzyme N-acetylglucosaminidase was unchanged by free-AMB. Incorporation of AMB into liposomes prevented the toxic effects of free-AMB on glomerular filtration and tubular cells membrane, but significantly increased N-acetylglucosaminidase urinary excretion (380 and 180% in animals receiving 4 and 10 mg/kg of L-AMB, respectively). Absolute AMB urinary excretion during the experiment was unchanged by liposomes and was always less than 1% of the total dose administered. Liposomes alone exhibited no toxicity. These results suggest that liposomes could increase the interaction between AMB and lysosomes leading to an additional mechanism of cellular injury. They admonish close monitoring of renal function and enzymuria in clinical situations in which L-AMB is being used.
Joly
V
V
Laboratoire d'Etude des Traitements Antiinfectieus, Faculte X, Bichat, Université Paris VII, Institut National de la Santé et de Recherche Médicale, France.
Dromer
F
F
Barge
J
J
Yeni
P
P
Seta
N
N
Molas
G
G
Carbon
C
C
D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D004337:Drug Carriers; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology; D007684:Kidney Tubules / Q000187:drug effects; D008081:Liposomes; D008297:Male; D011817:Rabbits
D004337:Drug Carriers; D008081:Liposomes; D000666:Amphotericin B