Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals

• Published in: Xenobiotica Vol. 43; no. 2; pp. 182 - 192
• Main Authors: Kawaguchi, Naohiro, Ebihara, Takuya, Takeuchi, Toshiyuki, Morohashi, Akio, Yamasaki, Hitomi, Tagawa, Yoshihiko, Takahashi, Junzo, Kondo, Takahiro, Asahi, Satoru
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.02.2013; Taylor & Francis
• Subjects: Administration, Oral; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics; Animals; Azilsartan medoxomil; Benzimidazoles - administration & dosage; Benzimidazoles - metabolism; Benzimidazoles - pharmacokinetics; Caco-2; Caco-2 Cells; Carbon Radioisotopes - blood; Cell Membrane Permeability; Dogs; Humans; Hydrolysis; Intestinal Absorption; Intestines - metabolism; Liver - metabolism; Male; medoxomil moiety; Oxadiazoles - administration & dosage; Oxadiazoles - metabolism; Oxadiazoles - pharmacokinetics; permeability; prodrug; Rats; Rats, Wistar; Serum Albumin; TAK-536
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2012.708797

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 Tmax 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.