title: Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. Kawaguchi_Naohiro@takeda.co.jp
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Takuya
authors.initials: T
authors.lastname: Ebihara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Akio
authors.initials: A
authors.lastname: Morohashi
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Junzo
authors.initials: J
authors.lastname: Takahashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kondo
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes / Q000097:blood; D002463:Cell Membrane Permeability; D004285:Dogs; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; D010069:Oxadiazoles; D012709:Serum Albumin; C521273:azilsartan; C557413:azilsartan medoxomil