JAC Advance Access originally published online on December 4, 2003
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Journal of Antimicrobial Chemotherapy (2004) 53, 81-88
© 2004 The British Society for Antimicrobial Chemotherapy
Study of the toxicity of a new lipid complex formulation of amphotericin B
1 Laboratoire de Physico-chimie, Pharmacotechnie, Biopharmacie, UMR CNRS 8612 and 5 Laboratoire de Physiologie, Faculté de Pharmacie, 5 Rue J.B. Clément, 92296 Châtenay Malabry; 2 Faculté de Pharmacie, Route du Rhin, 67400 Illkirch; 3 Centre de Génétique Moléculaire, UPR CNRS 9061, 91198 Gif-sur-Yvette Cedex; 4 Hôpital J. Verdier, Laboratoire de Toxicologie, Avenue du 14 juillet, 93140 Bondy, France
Received 14 May 2003; returned 19 July 2003; revised 27 August 2003; accepted 16 October 2003
Objectives: The aim of this study was to evaluate the toxicity of a new lipid complex formulation of amphotericin B (LC-AmB) produced by a simple process.
Methods: Toxicity was evaluated after daily administration for 21 consecutive days in female CD1 mice. Doses of LC-AmB up to 20 mg/kg were used, and compared with Fungizone at 0.5 mg/kg and Abelcet at 10 mg/kg. Acute toxicity after a single bolus injection was also determined, as well as the haemolytic activity and toxicity to mouse macrophages in vitro.
Results: LC-AmB reduced both the haemolytic activity of amphotericin B and its toxicity towards mouse peritoneal macrophages. Its acute toxicity (LD50 > 200 mg/kg in CD1 mice) was similar to that in the literature for the least toxic lipid formulations of amphotericin B. The relative liver weight increased slightly in mice treated daily with a dose of 20 mg/kg LC-AmB, as did the kidney weight in this group and the group treated with Fungizone. There was also a dose-dependent decrease in the haematocrit with all formulations. All treatments caused significant increases in transaminase levels. Total hepatic CYP 450 was slightly but not significantly increased in the groups treated with 20 mg/kg LC-AmB, Abelcet and Fungizone. However, expression of some isoforms of CYP 450 was reduced, the most marked being the hepatic CYP 3A1 after treatment with 20 mg/kg LC-AmB, Abelcet and Fungizone. The effects on hepatic function are probably related to accumulation in organs rich in phagocytic cells.
Conclusion: LC-AmB did not induce any new toxicity compared with Abelcet and Fungizone.
Keywords: LD50, lipid complex, cytochrome P450, antifungal
* Corresponding author. Tel: +33-1-46-83-56-27; Fax: +33-1-46-61-93-34; E-mail: Gillian.Barratt{at}cep.u-psud.fr
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