Localization and disposition of a non-peptide angiotensin II type 1 receptor antagonist, and its glucuronide metabolite, in rat.

1. The disposition of radioactivity of a non-peptide angiotensin II type 1 receptor antagonist (E4177) has been studied in groups of male rats after a single oral 1 mg/kg dose of 14C-E4177 was administered by gavage. We have also used light-microscopic autoradiography to investigate the localization of radioactivity in the target tissues for this angiotensin II receptor antagonist. 2. The radioactivity was absorbed quickly, and the maximum blood levels (Cmax) were reached at 0.38 +/- 0.14 h after dosing. The concentrations then declined bi-exponentially with a mean apparent half-life for the first phase (t1/2 alpha) of 0.46 +/- 0.07 h and a terminal half-life (t1/2 beta) of 6.22 +/- 1.08 h. By 24 h, the levels had decreased to 2.7 +/- 1.5% Cmax. The blood levels radioactivity at 48 h after administration were below the limit of quantification. 3. Radioactivity was distributed throughout the body at 15 min after administration. Tissues in which radioactivity was present at higher levels than in plasma were the liver and kidney. Radioactivity was rapidly eliminated from the tissues and was not retained in any individual organ. 4. The major route of excretion was via the bile. Since > 90% of the administered radioactivity was recovered by 24 h after administration, the excretion was relatively rapid. The major metabolite in bile was a glucuronide of E4177 biphenylcarboxylic acid (E4177-Glu). 5. Light-microscopic autoradiographic observations revealed a strong localization of radioactivity throughout the surface cells of the adrenal glomerulosa, the blood vessels in kidney and the surface of the aortic smooth muscle cells, which are all rich in angiotensin II type 1 (AT1) receptors.