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Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans.

Abstract：

AIMS: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.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Verhaar MC,Grahn AY,Van Weerdt AW,Honing ML,Morrison PJ,Yang YP,Padley RJ,Rabelink TJ

doi

10.1046/j.1365-2125.2000.00171.x

keywords:

subject

Has Abstract

pub_date

2000-06-01 00:00:00

pages

562-73

issue

eissn

0306-5251

issn

1365-2125

pii

bcp171

journal_volume

pub_type

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Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans.