ABSTRACT
EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2 R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single 14 C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.
Subject(s)
Analgesics/pharmacokinetics , Angiotensin II Type 2 Receptor Blockers/pharmacokinetics , Benzhydryl Compounds/pharmacokinetics , Isoquinolines/pharmacokinetics , Analgesics/blood , Analgesics/chemistry , Analgesics/urine , Angiotensin II Type 2 Receptor Blockers/blood , Angiotensin II Type 2 Receptor Blockers/chemistry , Angiotensin II Type 2 Receptor Blockers/urine , Animals , Benzhydryl Compounds/blood , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/urine , Biotransformation , Blood Proteins/metabolism , Cells, Cultured , Dogs , Feces/chemistry , Female , Hepatocytes/metabolism , Humans , Isoquinolines/blood , Isoquinolines/chemistry , Isoquinolines/urine , Macaca fascicularis , Male , Mice, Inbred ICR , Microsomes, Liver/metabolism , Rats, Long-Evans , Rats, Sprague-Dawley , StereoisomerismABSTRACT
O transplante renal continua sendo o melhor tratamento para os pacientes com insuficiência renal crônica. Para tanto, é de grande importância a compreensão dos mecanismos imunológicos envolvidos no transplante de órgãos, por todos aqueles envolvidos na assistência desses pacientes. Este estudo têm por objetivos identificar os diagnósticos de enfermagem mais freqüentes nos pacientes transplantados renais, frente as alterações orgânicas e imunológicas decorrentes do transplante e da terapêutica imunossupressora e elaborar um plano de assistência de enfermagem pós-transplante renal na fase hospitalar...
Subject(s)
Nursing Diagnosis , Transplantation Immunology , Graft Rejection , Kidney TransplantationABSTRACT
O transplante renal continua sendo o melhor tratamento para os pacientes com insuficiência renal crônica. Para tanto, é de grande importância a compreensão dos mecanismos imunológicos envolvidos no transplante de órgãos, por todos aqueles envolvidos na assistência desses pacientes
