RESUMO
Gonadotropin-releasing hormone (GnRH) receptor antagonists are an important class of compounds designed to block the pituitary gland from synthesizing follicle-stimulating hormone and luteinizing hormone for the treatment of sex hormone dependent disorders. Elagolix (ABT-620) is currently approved for the treatment of pain associated with endometriosis and as a combination with estradiol and norethindrone acetate is approved for management of heavy menstrual bleeding due to uterine fibroids. In order to support the development of elagolix, we prepared [3 H]elagolix for preclinical metabolism studies and [14 C]elagolix for environmental risk assessment studies.
Assuntos
LeiomiomaRESUMO
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
Assuntos
Materiais Biocompatíveis/síntese química , Portadores de Fármacos/síntese química , Fígado/metabolismo , Nylons/síntese química , Peptídeos/síntese química , RNA Interferente Pequeno/administração & dosagem , Animais , Autorradiografia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Desenho de Fármacos , Estabilidade de Medicamentos , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Fígado/diagnóstico por imagem , Macaca mulatta , Nylons/química , Nylons/farmacocinética , Nylons/toxicidade , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/toxicidade , Cintilografia , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The disposition of vorinostat, an anticancer agent, was investigated in rats and dogs. Vorinostat possessed high serum clearance, a short elimination half-life and low oral bioavailability in both species. The renal route played an important role in the elimination of drug-related material and vorinostat was eliminated primarily by metabolic biotransformation.