Pharmacokinetic and pharmacodynamic effects of YM087, a combined V-1/V-2 vasopressin receptor antagonist in normal subjects

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 V-1/V-2 re ceptor antagonist were characterised in healthy normotensive subjects. Methods: Six subjects were randomly allocated to receive, at 1-week interva ls, 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. Up on 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 l ess than 100-mosmol/l) were observed with a peak effect 2 h after drug inta ke suggesting effective vasopressin V-2 receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 +/- 1.3 mosmol/l to 28 8 +/- 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 V-1 receptors. However, the YM087-induced antagonism of V-1 r eceptors was less pronounced than V-2 receptor blockade. Conclusion: These data show that YM087 is an effective dual V-1/V-2 recepto r antagonist in man.