Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals.
Xenobiotica
; 43(2): 182-92, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-22867273
ABSTRACT
The absorption process in animals of TAK-491, designed as ester-based prodrug with medoxomil moiety, was evaluated. In the plasma of rats and dogs, TAK-536, the pharmacologically active metabolite, was present as the main component with hardly detectable concentrations of TAK-491 after oral administration of TAK-491. In the rat portal plasma, TAK-536 was also present as the main component with hardly detectable concentrations of TAK-491 after jejunal loop injection of TAK-491, suggesting TAK-491 was absorbed from small intestine and hydrolyzed almost completely during absorption. Caco-2 study indicated the permeability of TAK-491 was improved by prodrug modification and the compound could be mainly transferred as TAK-491. This is well consistent with the facts that the AUC and T(max) of TAK-536 after oral administration of TAK-491 were higher and shorter than those after oral administration of TAK-536 in dogs Hydrolysis of TAK-491 is observed not only by the intestinal and hepatic S9 fraction, but also by plasma and human serum albumin. However, medoxomil alcohol wasn't detected during the hydrolysis of TAK-491. These metabolic features of TAK-491 were similar to olmesartan medoxomil, suggesting the hydrolytic pathway and enzymes for TAK-491 when catalyzing to TAK-536 would be the same as olmesartan medoxomil.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxidiazóis
/
Benzimidazóis
/
Bloqueadores do Receptor Tipo 1 de Angiotensina II
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Japão