PHARMACOKINETICS, METABOLISM AND PHARMACODYNAMICS OF A BENZIMIDAZOLE ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONIST IN THE BEAGLE DOG AND CYNOMOLGUS MONKEY

1. The pharmacokinetics and disposition of E4177, an angiotensin II (A ng II) type 1 receptor antagonist, were studied in the beagle dog and cynomologus monkey following intravenous (i.v.) and oral (p.o.) admini stration. The relationship between the plasma concentrations of E4177 and Ang II receptor blockade were investigated in both species. 2. Sin gle 0.3 mg/kg i.v. doses of E4177 in dog and monkey were eliminated ra pidly. The elimination half-lives were 1.9 and 2.0 h, and the systemat ic plasma clearance values were 9.1 and 12.9 ml/min/kg respectively. 3 . The oral bioavailability of single doses of 0.3-3 mg/kg of E4177 was > 60 % in both dog and monkey. The absorption by both species was rap id, with peak plasma levels observed within 1 h, and the areas under t he concentration versus time curve to infinity were proportional to th e dose. 4. The apparent volumes of distribution at the steady-state we re 1.0 and 1.21/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 elimination pathway for radioactivity (approximately 90% of the dose) in both species after 1 mg/kg p.o. adm inistration of C-14-E4177. Unchanged E4177 was the major radioactive c omponent in the urine and faeces (0-24 h) of both species, accounting for approximately 85% of dose. In monkey, a minor metabolite in excret a and plasma was identified as the phase I metabolite M1, which is pro duced from E4177 by methyl-hydroxylation. M1 was not detected in dog. 6. The unbound plasma concentration versus blockade of the exogenous A ng II-induced vasopressor response was also determined after an i.v. a dministration of 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 di fferent: 2.6 and 2.7 ng/ml respectively.