Abstract
Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.
Highlights
As far as leishmaniasis therapy is concerned, tartar emetic and other SbIII-based drugs were replaced by sodium stibogluconate (SSG) (Pentostam®) and meglumine antimoniate (MA) (Glucantime®), less toxic stibogluconate are pentavalent antimony (SbV) drugs that were introduced in the market in mid 1940s (Haldar et al 2011)
Data on speciation of Sb in monkeys’ plasma one and nine days after a 21-day treatment course with MA indicated that the proportion of SbIII in nadir plasma levels of Sb markedly increased with time during the slow elimination phase, a finding that is consistent with the hypothesis that SbIII becomes a major Sb species during the terminal elimination phase (Friedrich et al 2012)
Six rats were treated with MA (300 mg SbV/kg body wt/d, s.c.) for 21 days and their Sb blood levels were measured on the day following the last dose of MA and 105 days later
Summary
As far as leishmaniasis therapy is concerned, tartar emetic and other SbIII-based drugs were replaced by sodium stibogluconate (SSG) (Pentostam®) and meglumine antimoniate (MA) (Glucantime®), less toxic SbV drugs that were introduced in the market in mid 1940s (Haldar et al 2011). According to Chulay et al (1988), their data on Sb blood levels could be described by a two-compartment kinetic model the slow elimination phase of which had a half-life of 76 h. Despite the recent advances in the knowledge of antimonial drug kinetics, little is known about the distribution of Sb into tissues of individuals treated with SbIII or SbV compounds. Molokhia and Smith (1969) measured (by neutron activation analysis) the Sb content of tissues of Schistosoma mansoni-infected mice at different time intervals (0.5 h, 8 h, 24 h, 2, 4, 7 and 15 days) after a single intraperitoneal (i.p.) injection of a SbIII drug (tartar emetic or sodium antimony 2,3 mesodimercapto-succinate, Astiban®). Levels of Sb were low in all tissues of mice euthanised on post-treatment day 4 and thereafter
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