The pharmacokinetics and metabolism of DuP 532, a non‐peptide angiotensin II receptor antagonist, in rats and dogs

Abstract

DuP 532, 2-propyl-4-pentafluoroethyl-1-([2'-(1H-tetrazol-5-yl)biph eny l-4-]methyl) imidazole-5-carboxylic acid, is an orally active, non-peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half-life averaged 8.0% and 3.5 h, respectively, after the sodium bicarbonate solution and 7.6% and 3.6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11.9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs. The in vitro metabolism of 14C-DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

“…However, like other diacids the oral bioavailability of DMP 811 is moderate, ca. 8% and 13% when administered as a neat powder to rats and dogs, respectively, which is similar to that of DuP 532. ,− …”

“…8% and 13% when administered as a neat powder to rats and dogs, respectively, which is similar to that of DuP 532. 62,[97][98][99] Like losartan, DMP 581 (an imidazolecarboxaldehyde) is a competitive antagonist, while DMP 811 and other diacids such as DuP 532 and EXP3174 behave as noncompetitive antagonists, 96,99 that is, these compounds cause nonparallel rightward shifts of the Ang II concentration-contractile response curves and reduce the maximal contractile response to Ang II by 30-40% 68,99 in the functional assay (isolated rabbit aorta). This phenomenon may be the result of a slow off-rate of bound antagonist from the receptor.…”

Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

“…10 This was attributed to poor absorption from the gastrointestinal (GI) tract rather than to other factors such as extensive first-pass metabolism. 11 The presence of two acid functionalities was put forth as a possible cause for poor absorption in a related series of compounds, in which the imidazolic carboxylic acid group was replaced by a carboxamide, leading to a compound of high oral bioavailability. 12 A series of pyrazole derivatives III, explored independently by Glaxo 13 and Merck, 14 also provided highly potent compounds.…”

The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

“…Bioavailability of CP-191,166 in rat (95%) was significantly higher than both losartan (F =33%) [10] and DuP 532 (DuPont Merck, Wilmington, Delaware) (F=8%) [11] following single oral dosing. CP-191,166 (F= 50%) had higher bioavailability than losartan [12] (F= 27%) or DuP 532 [11] (F= 11.9-13.4%) in dogs following a single oral dose. The oral plasma half-life for the Pfizer compound in dog was 9 h, which is longer than the 2.2-h oral t 1/2 reported for losartan and the 4-h oral t 1/2 reported for DuP 532.…”