Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals.
Summary of "Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals."
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.
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.
This article was published in the following journal.
Name: Xenobiotica; the fate of foreign compounds in biological systems
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22867273
- DOI: http://dx.doi.org/10.3109/00498254.2012.708797
Medical and Biotech [MESH] Definitions
Receptor, Angiotensin, Type 2
An angiotensin receptor subtype that is expressed at high levels in fetal tissues. Many effects of the angiotensin type 2 receptor such as VASODILATION and sodium loss are the opposite of that of the ANGIOTENSIN TYPE 1 RECEPTOR.
An antagonist of ANGIOTENSIN TYPE 1 RECEPTOR with antihypertensive activity due to the reduced pressor effect of ANGIOTENSIN II.
Angiotensin Receptor Antagonists
Agents that antagonize ANGIOTENSIN RECEPTORS. Many drugs in this class specifically target the ANGIOTENSIN TYPE 1 RECEPTOR.
An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the C-terminal by ANGIOTENSIN CONVERTING ENZYME. The amino acid in position 5 varies in different species. To block VASOCONSTRICTION and HYPERTENSION effect of angiotensin II, patients are often treated with ACE INHIBITORS or with ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS.
Receptor, Angiotensin, Type 1
An angiotensin receptor subtype that is expressed at high levels in a variety of adult tissues including the CARDIOVASCULAR SYSTEM, the KIDNEY, the ENDOCRINE SYSTEM and the NERVOUS SYSTEM. Activation of the type 1 angiotensin receptor causes VASOCONSTRICTION and sodium retention.
In the updated concept of renin-angiotensin system (RAS), it contains the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angtiogensin type 1 receptor (AT1) axis and the angiotensin-convertin...
Aim: The aim was to investigate effects of selective endothelin (ET) receptor antagonists on renal hemodynamics and dynamic renal blood flow autoregulation (RBFA) in angiotensin II (Ang II)-infused ra...
Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pr...
The goals of this study were to: 1) determine the acute effect of angiotensin 1-7 on vascular tone in isolated middle cerebral arteries (MCA) from Sprague-Dawley rats fed a normal salt (NS; 0.4% NaCl)...
Metabolic regulation plays an important role in modifying coronary vascular tone. We hypothesized that hydrogen peroxide, purinergic components, and angiotensin, produced by cardiac myocytes control c...
The antihypertensive effect of the increased dose of angiotensin II receptor blocker (AII antagonist) is compared with that of the additional combined use of amlodipine in hypertensive pat...
The purpose of this study is to investigate which combination therapy is more effective in reducing the incidence of cardiovascular events in Japanese elderly high-risk hypertensive patien...
This feasibility study is designed to examine modulation of the relative activities of ACE and ACE2 in diabetic patients following treatment with the angiotensin type 1 receptor (AT1R) ant...
In this study we hypothesize that blocking the angiotensin II AT1-receptor improves the insulin-induced microvascular dilatation. Objectives: 1. Does blockade of the angiotensin II AT1-rec...
The purpose of this study is to elucidate whether or not angiotensin II receptor blockers (ARB) are more beneficial or equal to angiotensin converting enzyme inhibitors (ACEI) on developme...