Pharmacokinetics, metabolism and pharmacodynamic s of a benzimidazole angiotensin II type 1 receptor antagonist in the beagle dog and cynomologus monkey

Abstract

1. The pharmacokinetic s and disposition of E4177, an angiotensin II (Ang II) type 1 receptor antagonist, were studied in the beagle dog and cynomologus monkey following intravenous (i.v.) and oral (p.o.) administration. The relationship between the plasma concentrations of E4177 and Ang II receptor blockade were investigated in both species.

2. Single 0.3 mg kg i.v. doses of E4177 in dog and monkey were eliminated rapidly. The elimination half-lives were 1.9 and 2.0 h, and the systematic plasma clearance values were 9.1 and 12.9 ml/min/kg respectively.

3. The oral bioavailabilityof single doses of 0.3-3 mg/kg of E4177 was > 60% in both dog and monkey. The absorption by both species was rapid, with peak plasma levels observed within 1 h, and the areas under the concentration versus time curve to infinity were proportional to the dose.

4. The apparent volumes of distributionat the steady-state were 1.0 and 1.2 l/kg in dog and monkey respectively. Tissue penetration was probably limited by the relatively high binding to plasma proteins (approximately 92.0 and 98.6% in the dog and monkey respectively).

5. Faecal excretion was the major eliminationpathway for radioactivity(approximately 90% of the dose) in both species after 1 mg/kg p.o. administration of ¹⁴C-E4177. Unchanged E4177 was the major radioactive component in the urine and faeces (0-24 h) of both species, accounting for approximately 85% of dose. In monkey, a minor metabolitein excreta and plasma was identified as the phase I metabolite M1, which is produced from E4177 by methyl- hydroxylation. M1 was not detected in dog. 6. The unbound plasma concentration versus blockade of the exogenous Ang IIinduced vasopressor response was also determined after an i.v. administrationof E4177 to dog and monkey. The relationship between the unbound E4177 concentration and the effect was highly significant in both species. The IC₅₀ of the dog and monkey were not significantly different: 2.6 and 2.7 ng/ml respectively.