Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals

J. Nieto, J. Alvar, A. Mullen, K.C. Carter, C. Rodriguez, M.I. San Andres, M.D. San Andres, A.J. Baillie

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 (V-SS) was also increased (V-SS for SSG, 0.21 liters/kg; V-SS 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.
LanguageEnglish
Pages2781-2787
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume47
Issue number9
DOIs
Publication statusPublished - Sep 2003

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Antimony Sodium Gluconate
Intravenous Administration
Pharmacokinetics
Dextrans
Dogs
Pharmaceutical Preparations

Keywords

  • encapsulated meglumine antimonate
  • visceral leishmaniasis
  • canine leishmaniasis
  • amphotericin-b
  • balb/c mouse
  • dogs
  • complement
  • donovani
  • mice
  • disposition

Cite this

Nieto, J. ; Alvar, J. ; Mullen, A. ; Carter, K.C. ; Rodriguez, C. ; San Andres, M.I. ; San Andres, M.D. ; Baillie, A.J. / Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals. In: Antimicrobial Agents and Chemotherapy . 2003 ; Vol. 47, No. 9. pp. 2781-2787.
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abstract = "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 (V-SS) was also increased (V-SS for SSG, 0.21 liters/kg; V-SS 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.",
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Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals. / Nieto, J.; Alvar, J.; Mullen, A.; Carter, K.C.; Rodriguez, C.; San Andres, M.I.; San Andres, M.D.; Baillie, A.J.

In: Antimicrobial Agents and Chemotherapy , Vol. 47, No. 9, 09.2003, p. 2781-2787.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals

AU - Nieto, J.

AU - Alvar, J.

AU - Mullen, A.

AU - Carter, K.C.

AU - Rodriguez, C.

AU - San Andres, M.I.

AU - San Andres, M.D.

AU - Baillie, A.J.

N1 - Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.

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Y1 - 2003/9

N2 - 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 (V-SS) was also increased (V-SS for SSG, 0.21 liters/kg; V-SS 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.

AB - 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 (V-SS) was also increased (V-SS for SSG, 0.21 liters/kg; V-SS 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.

KW - encapsulated meglumine antimonate

KW - visceral leishmaniasis

KW - canine leishmaniasis

KW - amphotericin-b

KW - balb/c mouse

KW - dogs

KW - complement

KW - donovani

KW - mice

KW - disposition

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U2 - 10.1128/AAC.47.9.2781-2787.2003

DO - 10.1128/AAC.47.9.2781-2787.2003

M3 - Article

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SP - 2781

EP - 2787

JO - Antimicrobial Agents and Chemotherapy

T2 - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

ER -