Kinetics of antimony(V) reduction by L-cysteine: pharmacological implications and application to the determination of antimony in pentavalent antimonial drugs

Abstract

Como o antimônio é a espécies ativa no medicamento leishmanicida, antimoniato de meglumina (AM), o conhecimento da concentração exata do metal é crítico para o seu uso experimental e clínico. Por outro lado, o papel da cisteína no metabolismo dos antimoniais deve ser esclarecido. No presente trabalho, a reação de redução do Sb V pela cisteína foi caracterizada cineticamente. As ordens de reação com relação ao Sb e à cisteína foram iguais a 1,0 e 3,3, respectivamente. A constante de velocidade da reação de redução foi dependente do pH. Essa reação foi usada para reduzir o Sb V no AM, para subseqüente determinação fotométrica do Sb III com o cromóforo vermelho de bromopirogalol. Eficiências de redução de 100% foram alcançadas em pH 3. Soluções apresentando concentrações de Sb baixas como 0,5 mmol L -1 foram dosadas com sucesso. O método foi também aplicado para a determinação de Sb em formulações lipossomais do AM.Since antimony is the active species in the antileishmanial drug meglumine antimoniate (MA), the knowledge of the exact metal concentration is critical for its experimental and clinical use. On the other hand, the involvement of thiols, such as cysteine (Cys), in the metabolism of this drug remains to be clarified. In the present work, the reduction reaction of Sb V by Cys was kinetically characterized. The reaction orders with respect to Sb and Cys were equal to 1.0 and 3.3, respectively. The rate constant for the reduction reaction was pH-dependent. This reaction was exploited to effectively reduce Sb V in MA, for the subsequent photometric determination of Sb III using the chromogen bromopyrogallol red. Reduction efficiencies of 100% were achieved at pH 3. Solutions with Sb concentration as low as 0.5 mmol L -1 were successfully assayed. The method was also applied to the determination of Sb in liposomal formulations of MA.

Reduced Tissue Parasitic Load and Infectivity to Sand Flies in Dogs Naturally Infected by Leishmania ( Leishmania ) chagasi following Treatment with a Liposome Formulation of Meglumine Antimoniate

“…The liposome pellet was then washed twice and finally resuspended in isotonic saline at a final antimony concentration of about 10 g/liter. The concentration of encapsulated antimony and the phospholipid concentration in the resulting liposome suspension were determined using previously described colorimetric assays (34,38). The drug encapsulation efficiency and the final Sb/lipid ratio were equal to 40% Ϯ 4% and 0.25:1 (wt/wt), respectively.…”

Gold nanoparticles as a colorimetric probe for the determination of N-acetyl-l-cysteine in biological samples and pharmaceutical formulations

“…However, the interference of Ca 2+ , Cd 2+ , Mg 2+ and Ni 2+ were eliminated using ethylenediaminetetraacetic acid (EDTA). Because antimony (Sb) is the active species in some commercial formulations for the treatment of some disease such as leishmaniasis, 28 the interference of Sb 3+ and Sb(V) was also studied. In addition, the selectivity of the proposed method to glutathione (GSH) was also investigated.…”

Report on Carcinogens Monograph on Antimony Trioxide

“…Evidence for reduction of antimony(V) to antimony(III) in humans is based on detection of both antimony(III) and antimony(V) in the urine of people injected with meglumine antimoniate(V) (Glucantime) (Miekeley et al 2002;Petit de Peña et al 1990), consistent with release of anionic antimony(V) from the drug and possible reduction to antimony(III) in vivo. The kinetics of reduction of antimony(V) from the antileishmanial drug meglumine antimoniate to antimony(III) by L-cysteine in vitro indicate a peak rate constant at pH 4.7, which is consistent with the pH range of 4.5 to 5.0 within lysosomes, where the drug is believed to act (De Oliveira et al 2006). Reduction of antimony(V) to antimony(III) in various types of human cells in vitro is consistent with this finding.…”