title: Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals.
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.
authors.affiliation: WHO Collaborating Center for Leishmaniasis Servicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Spain. fjnieto@isciii.es
authors.forename: J
authors.initials: J
authors.lastname: Nieto
authors.forename: J
authors.initials: J
authors.lastname: Alvar
authors.forename: A B
authors.initials: AB
authors.lastname: Mullen
authors.forename: K C
authors.initials: KC
authors.lastname: Carter
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez
authors.forename: M I
authors.initials: MI
authors.lastname: San Andrés
authors.forename: M D
authors.initials: MD
authors.lastname: San Andrés
authors.forename: A J
authors.initials: AJ
authors.lastname: Baillie
authors.forename: F
authors.initials: F
authors.lastname: González
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000967:Antimony Sodium Gluconate / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000097:blood; D002626:Chemistry, Pharmaceutical; D003911:Dextrans; D004285:Dogs; D005079:Excipients; D005260:Female; D007275:Injections, Intravenous; D007501:Iron / Q000097:blood; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013501:Surface-Active Agents; D013535:Suspensions
chemical_list: D000981:Antiprotozoal Agents; D003911:Dextrans; D005079:Excipients; D013501:Surface-Active Agents; D013535:Suspensions; D007501:Iron; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D000967:Antimony Sodium Gluconate