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Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: e00489-18. doi: 10.1128/AAC.00489-18. Print 2018 Jul.

Efficacy, Biodistribution, and Nephrotoxicity of Experimental Amphotericin B-Deoxycholate Formulations for Pulmonary Aspergillosis.

Author information

1
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Universidad Complutense, Madrid, Spain.
2
Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili and Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain.
3
Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain.
4
Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain.
5
Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain.
6
Instituto Universitario de Farmacia Industrial, Universidad Complutense, Madrid, Spain.
7
Department of Microbiology and Parasitology, Faculty of Pharmacy, Universidad Complutense, Madrid, Spain.
8
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Universidad Complutense, Madrid, Spain storrado@ucm.es.

Abstract

An experimental micellar formulation of 1:1.5 amphotericin B-sodium deoxycholate (AMB:DCH 1:1.5) was obtained and characterized to determine its aggregation state and particle size. The biodistribution, nephrotoxicity, and efficacy against pulmonary aspergillosis in a murine model were studied and compared to the liposomal commercial formulation of amphotericin B after intravenous administration. The administration of 5 mg/kg AMB:DCH 1:1.5 presented 2.8-fold-higher lung concentrations (18.125 ± 3.985 μg/g after 6 daily doses) and lower kidney exposure (0.391 ± 0.167 μg/g) than liposomal commercial amphotericin B (6.567 ± 1.536 and 5.374 ± 1.157 μg/g in lungs and kidneys, respectively). The different biodistribution of AMB:DCH micelle systems compared to liposomal commercial amphotericin B was attributed to their different morphologies and particle sizes. The efficacy study has shown that both drugs administered at 5 mg/kg produced similar survival percentages and reductions of fungal burden. A slightly lower nephrotoxicity, associated with amphotericin B, was observed with AMB:DCH 1:1.5 than the one induced by the liposomal commercial formulation. However, AMB:DCH 1:1.5 reached higher AMB concentrations in lungs, which could represent a therapeutic advantage over liposomal commercial amphotericin B-based treatment of pulmonary aspergillosis. These results are encouraging to explore the usefulness of AMB:DCH 1:1.5 against this disease.

KEYWORDS:

amphotericin B; aspergillosis; deoxycholate; efficacy; nephrotoxicity; pulmonary concentrations

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