Unexpectedly high levels of antimony (III) in the pentavalent antimonial drug Glucantime: insights from a new voltammetric approach

• Published in: Analytical and bioanalytical chemistry Vol. 405; no. 15; pp. 5201 - 5214
• Main Authors: Salaun, Pascal, Frezard, Frederic
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2013; Springer; Springer Nature B.V
• Subjects: Analytical Chemistry; Anti-infective agents; Antimony; Antimony - chemistry; Biochemistry; Characterization and Evaluation of Materials; Chemical properties; Chemistry; Chemistry and Materials Science; Composition; Detection limits; Drugs; Electrochemical Techniques - methods; Electrodes; Food Science; Identification and classification; Laboratory Medicine; Leishmania; Mathematical analysis; Meglumine - chemistry; Metabolites; Methods; Mode of action; Monitoring/Environmental Analysis; Organometallic Compounds - chemistry; Osmolar Concentration; Oxidation; Oxidation rate; Parasites; Parasitic diseases; Pharmaceutical chemistry; Protozoa; Research Paper; Side effects; Stripping; Tropical diseases; Vector-borne diseases; Voltammetry; United Kingdom; Electroanalytical methods; Inorganic compounds/trace inorganic compounds; Stripping analysis; Speciation; Electrochemical sensors; Solid electrodes
• ISSN: 1618-2642; 1618-2650
• DOI: 10.1007/s00216-013-6947-5

Glucantime, a pentavalent antimonial drug, is commonly used for the treatment of leishmaniasis but the presence of residual trivalent antimony, Sb(III), is thought to be responsible for toxic side-effects observed in patients. Numerous analytical studies have focused on determining Sb(III) concentrations in Glucantime but without reaching a consensus: results span over 3 orders of magnitude. In this study, we present a detailed new analytical approach showing that: (1) Sb(III) levels are much higher than previously reported and represent more than 30 % of total Sb; (2) determination of Sb(III) concentrations in acidic conditions is hampered by fast oxidation rates. This latter point explains the large variations in previously reported results of Sb(III) concentrations in Glucantime. Measurements were made here at a vibrated gold microwire electrode by stripping voltammetry enabling measurement of Sb(III) in acidic, neutral or alkaline conditions. The developed methods are sensitive (e.g., detection limits of 19 pM for 120 s deposition at pH 4.5), stable (<6 %,
N
 = 100), precise (5 %,
N
 = 5) and robust (same electrode used for weeks) at all pH values. In diluted solutions of Glucantime, Sb(III) levels were strongly dependent both on pH and ionic strength. At pH < 3, Sb(III) is oxidized with oxidation rates that increase as pH is decreased. At high pH, Sb(III) forms electro-inactive complexes. Highest Sb(III) levels were detected at pH ∼3 and at low ionic strength. The presence of several Sb(III) and Sb(V) species was demonstrated by different reduction waves obtained by stripping scanned voltammetry. As an implication of these unexpectedly high Sb(III) concentrations, an alternative model can be proposed for the mode of action of pentavalent antimonials against leishmaniasis, in which antimony complexes may act as molecular carrier of Sb(III) and release it specifically in the acidic intracellular compartment where the
Leishmania
parasites reside.