JAC Advance Access published online on December 4, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh025
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Laboratoire de Physico-chimie,
Pharmacotechnie, Biopharmacie, UMR CNRS 8612
* Corresponding author. E-mail: Gillian.Barratt{at}cep.u-psud.fr.
Received 14 May 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
Study of the toxicity of a new lipid complex formulation
of amphotericin B
2 Laboratoire de Physico-chimie,
Pharmacotechnie, Biopharmacie, UMR CNRS 8612 and Faculté de
Pharmacie,
Route du Rhin, 67400 Illkirch;
3 Faculté de
Pharmacie,
Route du Rhin, 67400 Illkirch;
4 Centre
de Génétique Moléculaire, UPR CNRS 9061,
91198 Gif-sur-Yvette Cedex;
5 Hôpital
J. Verdier, Laboratoire de Toxicologie, Avenue du 14 juillet, 93140
Bondy, France
6 Laboratoire de Physiologie, Faculté de
Pharmacie, 5 Rue J.B. Clément, 92296 Châtenay
Malabry;
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