RESUMO
A series of iron chelators, three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (DADFT) and three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (DADMDFT) analogues are synthesized and assessed for their lipophilicity (log Papp), iron-clearing efficiency (ICE) in rodents and iron-loaded primates (Cebus apella), toxicity in rodents, and organ distribution in rodents. The results lead to a number of generalizations useful in chelator design strategies. In rodents, while log Papp is a good predictor of a chelator's ICE, chelator liver concentration is a better tool. In primates, log Papp is a good predictor of ICE, but only when comparing structurally very similar chelators. There is a profound difference in toxicity between the DADMDFT and DADFT series: DADMDFTs are less toxic. Within the DADFT family of ligands, the more lipophilic ligands are generally more toxic. Lipophilicity can have a profound effect on ligand organ distribution, and ligands can thus be targeted to organs compromised in iron overload disease, for example, the heart.
Assuntos
Ácidos Carboxílicos/síntese química , Quelantes de Ferro/síntese química , Tiazóis/síntese química , Animais , Bile/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Cebus , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Quelantes de Ferro/química , Quelantes de Ferro/farmacologia , Complexo Ferro-Dextran/sangue , Complexo Ferro-Dextran/farmacocinética , Complexo Ferro-Dextran/urina , Rim/metabolismo , Fígado/metabolismo , Masculino , Miocárdio/metabolismo , Especificidade de Órgãos , Pâncreas/metabolismo , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Distribuição TecidualRESUMO
The elimination pattern and tissue distribution in rats of intravenous [14C-gluconic acid]-poly(sorbitol-gluconic acid) and 59Fe-iron-poly(sorbitol-gluconic acid) complex, glusoferron (Ferastral) have been examined. Twenty-four hours after injection of 20 or 200 mg/kg of [14C-gluconic acid]-poly(sorbitol-gluconic acid), 5%-6% of the injected dose of radiolabel was eliminated as 14CO2 and about 85% in the urine and faeces. Administration of 59Fe-iron-poly(sorbitol-gluconic acid) complex (10 and 100 mg of iron/kg) resulted in a urinary and faecal excretion of about 18% and 40% of the given dose, respectively, during the first 4 days. Biliary excretion was low. The mean molecular weight of the biliary product after the iron complex was lower than that of the parent compound. Radiocarbon in tissues after 24 hours was negligible. Liver and bones accounted for most of the retained radioiron following 100 mg of iron/kg bodyweight of the 59Fe-iron complex with maximum levels of 27% and 12% of the injected dose, respectively, 4 days after dosing. Red cell incorporation of 59Fe attained a level of 16% at the end of 28 days.
