In vitro renal toxicity and in vivo therapeutic efficacy in experimental murine cryptococcosis of amphotericin B (Fungizone) associated with Intralipid.
We compared the experimental toxicities and activities of deoxycholate amphotericin B (d-AmB) dissolved in glucose (Dd-AmB) or mixed with 20% Intralipid (ILd-AmB). In vitro, ILd-AmB against renal tubular cells in primary culture. In vivo, the toxicities and activities of Dd-AmB and ILd-AmB were studied in DBA2 mice with cryptococcosis. The maximum tolerated dose of intravenously administered d-AmB, i.e., the dose that induced less than 15% mortality because of toxicity, was 1.7 to 2.5 times higher when it was administered as ILd-AmB than when it was administered as Dd-AmB. Both treatments given intravenously at the same dose were equivalent for improving the survival of mice and reducing CFU counts in infected tissue, but at maximum tolerated doses, ILd-AmB (2 mg/kg of body weight) was more effective than Dd-AmB (0.8 to 1.2 mg/kg). AmB concentrations in spleen, liver, lung, and kidney were measured by high-pressure liquid chromatography 4 and 24 h after a single injection of 1.2 mg of Dd-AmB per kg, 1.2 mg of ILd-AmB per kg, or 2 mg of ILd-AmB per kg. In a given organ, AmB levels were similar after administration of 1.2 mg of Dd-AmB or ILd-AmB per kg but were significantly higher after administration of 2 mg of ILd-AmB per kg. The lower level of toxicity of ILd-AmB might be explained by circular dichroism experiments, showing that ILd-AmB contained 10-fold less soluble oligomeric AmB, which is believed to be the toxic form of the drug, than Dd-AmB. We conclude that ILd-AmB is as efficient as Dd-AmB and is better tolerated than Dd-AmB in mice with experimental cryptococcosis. By allowing higher doses of AmB to be infused, Intralipid enhances AmB concentrations in infected sites, and thus the therapeutic activity of the drug.
Joly
V
V
Laboratoire d'Etude des Infections Expérimentales, Faculté X, Bichat, Université Paris 7, France.
Farinotti
R
R
Saint-Julien
L
L
Chéron
M
M
Carbon
C
C
Yeni
P
P
D000666:Amphotericin B / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005217:Fat Emulsions, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced*; D007684:Kidney Tubules / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011817:Rabbits
D004337:Drug Carriers; D005217:Fat Emulsions, Intravenous; D000666:Amphotericin B