Characterization of the antimonial antileishmanial agent meglumine antimonate (glucantime)

Meglumine antimonate (Glucantime), a drug of choice for the treatment of leishmaniasis, is produced by the reaction of pentavalent antimony with N-methyl-D-glucamine, a carbohydrate derivative. We investigated the structure and composition of meglumine antimonate, which remain poorly understood, despite 50 years of use. Measurement of the antimony content of meglumine antimonate powder indicated a 1:1.37 molar ratio of antimony to N-methyl-D-glucamine. Osmolality measurements performed with meglumine antimonate solutions demonstrated an average of 1.43 antimony atoms per molecule of meglumine antimonate. The osmolality of a 1:10 dilution of stock meglumine antimonate increased by 45% over 8 days, suggesting hydrolysis to less complex species. A comparison of the proton nuclear magnetic resonance spectra of N-methyl-D-glucamine and meglumine antimonate revealed an increase in complexity in the latter but with all of the resonances of the former still being evident, consistent with the presence of coordination complexes between antimony and each of the N-methyl-D-glucamine hydroxyls. Fast atom bombardment and electrospray ionization mass spectrometry coupled with several derivatization procedures provided evidence that up to four N-methyl-D-glucamine hydroxyls are coordinated with each antimony. A series of oligomers were observed. The major moiety has a molecular mass of 507 atomic mass units and consists of NMG-Sb-NMG, where Sb represents antimony and NMG represents N-methyl-D-glucamine. Additional species containing up to four antimony atoms and five N-methyl-D-glucamine moieties and corresponding to the general form (NMG-Sb)n-NMG are also present. These results suggest that this agent is a complex mixture that exists in equilibrium in aqueous solution.