Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 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-p henylbenzanilide 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.


CONCLUSIONS
These data show that YM087 is an effective dual V1/V2 receptor antagonist in man.
Burnier
M
M
Department of Medicine, CHUV, Lausanne, Switzerland. Michel.Burnier@chuv.hospvd.ch
Fricker
A F
AF
Hayoz
D
D
Nussberger
J
J
Brunner
H R
HR
D000284:Administration, Oral; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009994:Osmolar Concentration; D012016:Reference Values; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014882:Water-Electrolyte Balance / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C106389:conivaptan