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Antimicrobial Agents and Chemotherapy, September 2003, p. 2781-2787, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2781-2787.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics, Toxicities, and Efficacies of Sodium Stibogluconate Formulations after Intravenous Administration in Animals

J. Nieto,1* J. Alvar,1 A. B. Mullen,2 K. C. Carter,3 C. Rodríguez,3 M. I. San Andrés,4 M. D. San Andrés,4 A. J. Baillie,2,{dagger} and F. González4

WHO Collaborating Center for Leishmaniasis Servicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda,1 Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain,4 Department of Pharmaceutical Sciences,2 Department of Immunology, University of Strathclyde, Glasgow, United Kingdom3

Received 1 March 2002/ Returned for modification 27 July 2002/ Accepted 3 June 2003

The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (VSS) was also increased (VSS for SSG, 0.21 liters/kg; VSS for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.

* Corresponding author. Mailing address: WHO Collaborating Center for Leishmaniasis, Servicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera de Majadahonda-Pozuelo, Km 2, 28220 Majadahonda, Spain. Phone: 34 91 509 79 01, ext. 3623. Fax: 34 91 509 70 34. E-mail: fjnieto{at}isciii.es.

{dagger} Present address: ProPharma Ltd., Glasgow, United Kingdom.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2781-2787, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2781-2787.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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