title: Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans.
abstract: OBJECTIVE
  Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans.
  
  
  METHODS
  Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2-40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed.
  
  
  RESULTS
  ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62% vs 4% during placebo, P < 0.05, for Study 1 and in 42% vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at approximately 1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 +/- 1 vs 19 +/- 1, 18 +/- 2 vs 23 +/- 3, 15 +/- 1 vs 17 +/- 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 +/- 2 vs 84 +/- 3, 80 +/- 4 vs 90 +/- 5, 75 +/- 3 vs 79 +/- 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level).
  
  
  CONCLUSIONS
  The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease.
authors.affiliation: Department of Nephrology and Hypertension, University Hospital Utrecht, Kendle-U-gene Clinical Pharmacology, Utrecht, the Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Verhaar
authors.forename: A Y
authors.initials: AY
authors.lastname: Grahn
authors.forename: A W
authors.initials: AW
authors.lastname: Van Weerdt
authors.forename: M L
authors.initials: ML
authors.lastname: Honing
authors.forename: P J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Y P
authors.initials: YP
authors.lastname: Yang
authors.forename: R J
authors.initials: RJ
authors.lastname: Padley
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D000077868:Atrasentan; D001682:Biological Availability; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005542:Forearm / Q000098:blood supply; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012039:Regional Blood Flow / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan