Pharmacokinetic and pharmacodynamic effects of YM087, a combined V₁/V₂ vasopressin receptor antagonist in normal subjects

Abstract

Objective: The pharmacokinetic and pharmacodynamic properties of YM087, (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a new orally active, dual V₁/V₂ receptor antagonist were characterised in healthy normotensive subjects.

Methods: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study.

Results: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V₂ receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 ± 1.3 mosmol/l to 288 ± 1.0 mosmol/l after i.v. and from 283 ± 2.1 mosmol/l to 289 ± 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 ± 0.3 pg/ml to 3.7 ± 0.6 pg/ml after i.v. and from 0.9 ± 0.1 pg/ml to 3.9 ± 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V₁ receptors. However, the YM087-induced antagonism of V₁ receptors was less pronounced than V₂ receptor blockade.

Conclusion: These data show that YM087 is an effective dual V₁/V₂ receptor antagonist in man.