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JAC Advance Access published online on June 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg266
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

Comparative pharmacokinetics and safety of a novel lyophilized amphotericin B lecithin-based oil-water microemulsion and amphotericin B deoxycholate in animal models

Begoña Brime 1 *, Paloma Frutos 1 , Pilar Bringas 2 , Ana Nieto 3 , M. Paloma Ballesteros 1 , and Gloria Frutos 4

1 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy;
2 Laboratory of Animal Facilities;
3 Department of Animal Pathology II, Faculty of Veterinary;
4 Department of Statistics and Operational Research, Complutense University of Madrid, 28040 Madrid, Spain

* Corresponding author. E-mail: begonab{at}farm.ucm.es.

Received 21 June 2002 ; revised 24 February 2002 ; accepted 2 April 2003

Abstract

Amphotericin B (AmB) has been a most effective systemic antifungal agent, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation Fungizone (D-AmB). To lower AmB-associated toxicity, AmB may be integrated into oil-in-water lecithin-based microemulsions. The present study compares the pharmacokinetic characteristics of D-AmB with the alternative formulation of AmB in microemulsion (M-AmB), which has proved effective in a murine candidiasis model. Both formulations were given by intravenous bolus: D-AmB 1 mg/kg, and M-AmB 0.5, 1 or 2 mg/kg. The pharmacokinetics of D-AmB and M-AmB have several differences, specifically with regard to the respective Cmax and AUC0-{infty} values. Elimination of AmB from serum was biphasic for both M-AmB and D-AmB. Single-dose D-AmB (1 mg/kg) achieved a Cmax of 3.89 ± 0.48 mg/L and an AUC0-{infty} of 32.28 ± 7.31 mg·h/L, whereas single-dose M-AmB (1 mg/kg) by comparison achieved a lower Cmax (2.92 ± 0.54 mg/L) and a lower AUC0-{infty} (21.89 ± 5.17 mg·h/L). To evaluate the safety of M-AmB, a multiple-dose toxicity study was performed in groups of 10 mice, each receiving D-AmB 1 mg/kg, or M-AmB 1, 1.5, 2 or 3 mg/kg. The findings suggest that, in comparison with D-AmB, M-AmB produces no histologically demonstrable renal lesions, or changes in clinical chemistry.

Keywords: amphotericin B, microemulsion, safety, pharmacokinetics, rabbits
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