Verhaar M C, Grahn A Y, Van Weerdt A W, Honing M L, Morrison P J, Yang Y P, Padley R J, Rabelink T J
Department of Nephrology and Hypertension, University Hospital Utrecht, Kendle-U-gene Clinical Pharmacology, Utrecht, the Netherlands.
Br J Clin Pharmacol. 2000 Jun;49(6):562-73. doi: 10.1046/j.1365-2125.2000.00171.x.
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.
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.
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).
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.
内皮素（ETs）可能在多种心血管疾病的发病机制中起作用。本研究旨在调查口服活性ETA选择性受体拮抗剂ABT - 627在健康人体内的药代动力学和药效学作用。
健康志愿者纳入两项采用交叉设计的研究。受试者接受单剂量或多剂量（为期8天）口服ABT - 627或匹配安慰剂，剂量范围为0.2 - 40毫克。描述了ABT - 627的药代动力学，并评估了其在静息状态下对全身血流动力学以及对ET - 1刺激引起的前臂血管收缩的影响。
在两项研究中ABT - 627总体耐受性良好，最常报告的不良事件为短暂性头痛（研究1中为62%，而安慰剂组为4%，P < 0.05；研究2中为42%，而安慰剂组为60%，P = 0.2）。ABT - 627吸收迅速，给药后约1小时达到血浆最高水平。单剂量20毫克和40毫克的ABT - 627在给药后8小时可抑制ET - 1诱导的前臂血管收缩。剂量为5毫克及以上的ABT - 627治疗8天也能有效阻断对ET - 1的前臂血管收缩反应。与安慰剂相比，ABT - 627使外周阻力显著降低（研究2中，1毫克、5毫克、20毫克时分别为16±1对19±1、18±2对23±3、15±1对17±1 AU），而血压仅轻度下降（研究二中，1毫克、5毫克、20毫克时分别为79±2对84±3、80±4对90±5、75±3对79±1）。ABT - 627使循环中免疫反应性ET水平呈中度剂量依赖性升高（在20毫克剂量水平时比基线水平最大升高50%）。
口服ETA受体阻滞剂ABT - 627耐受性良好，吸收迅速，有效阻断ET - 1诱导的血管收缩，并使总外周阻力和平均动脉压降低。我们的数据表明ABT - 627可能是治疗心血管疾病的一种有价值的工具。
