RESUMO
It has been previously reported that beta-cyclodextrin (beta-CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly used in association with beta-CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of beta-CD in this system requires clarification. ESI(-)-MS analysis of MA and of the MA/beta-CD composition indicated the formation of a 1:1 association compound between 1:1 Sb-meglumine complex and beta-CD. A stability constant on the order of 100 Lmol(-1) was determined for this association compound. When MA solution was heated for 48 h at 55 degrees C to mimic the conditions used to prepare MA/beta-CD, MA was found to suffer dissociation, from high molecular weight Sb complexes into species of lower molecular weight. Strikingly, heated MA was found to be more extensively absorbed in mice by the oral route than MA freshly prepared at room temperature. In vitro skin permeation experiments using MA and MA/beta-CD indicated a two-fold increase in the Sb flux for MA/beta-CD. These findings support the hypothesis that the improved oral absorption of Sb arises from the increased permeation of MA across lipid bilayers, as a result of the enhanced availability of 1:1 Sb-meglumine complex.
Assuntos
Meglumina/farmacocinética , Compostos Organometálicos/farmacocinética , Absorção Cutânea/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Dicroísmo Circular/métodos , Estabilidade de Medicamentos , Feminino , Bicamadas Lipídicas/metabolismo , Meglumina/química , Antimoniato de Meglumina , Camundongos , Peso Molecular , Compostos Organometálicos/química , Permeabilidade , Pele/efeitos dos fármacos , Pele/metabolismo , Solubilidade , Espectrometria de Massas por Ionização por Electrospray/métodos , Temperatura , Água/química , beta-Ciclodextrinas/químicaRESUMO
The need for daily parenteral administration represents one of the most serious limitations in the clinical use of pentavalent antimonials against leishmaniasis. In this work, we investigated the ability of beta-cyclodextrin to enhance the oral absorption of antimony and to promote the oral efficacy of meglumine antimoniate against experimental cutaneous leishmaniasis. The occurrence of interactions between beta-cyclodextrin and meglumine antimoniate was demonstrated through the changes induced in the spin lattice relaxation times of protons in both compounds. When free and complexed meglumine antimoniate were given orally to Swiss mice, plasma antimony levels were found to be about three times higher for the meglumine antimoniate-beta-cyclodextrin complex than for the free drug. Antileishmanial efficacy was evaluated in BALB/c mice experimentally infected with Leishmania amazonensis. Animals treated daily with the complex (32 mg of Sb/kg of body weight) by the oral route developed significantly smaller lesions than those treated with meglumine antimoniate (120 mg of Sb/kg) and control animals (treated with saline). The effectiveness of the complex given orally was equivalent to that of meglumine antimoniate given intraperitoneally at a twofold-higher antimony dose. The antileishmanial efficacy of the complex was confirmed by the significantly lower parasite load in the lesions of treated animals than in saline-treated controls. This work reports for the first time the effectiveness of an oral formulation for pentavalent antimonials.