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JAC Advance Access originally published online on June 12, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 103-109
© 2003 The British Society for Antimicrobial Chemotherapy

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

Begoña Brime1,*, Paloma Frutos1, Pilar Bringas2, Ana Nieto3, M. Paloma Ballesteros1 and Gloria Frutos4

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

Received 21 June 2002; returned 27 October 2002; revised 24 February 2003; accepted 2 April 2003

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

* Corresponding author. Tel: +34-91-394-17-22; Fax: +34-91-394-17-05; E-mail: begonab{at}farm.ucm.es


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