Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep
Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep
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DOI：
10.1111/j.1476-5381.2012.01904.x
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发表时间：
2012-07-01
影响因子：
7.3
通讯作者：
Richards, A. M.
中科院分区：
文献类型：
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作者：
Patel, K.;Rademaker, M. T.;Richards, A. M.
背景与目的尿皮质素（Ucn）肽正成为心脏病的潜在治疗靶点。然而，缺乏药代动力学（PK）和药效学（PD）数据。因此，我们研究了所有三种Ucns的PK/PD。实验方法7只羊分别注射1 μ g中心点kg-1剂量的Ucn1、Ucn2和Ucn3。建立了群体PK/PD模型来描述血流动力学效应的时间过程。结果Ucn1清除率（0.486 L中心点h-1）低于Ucn2 （21.7 L中心点h-1）和Ucn3 (220 L中心点h-1)，而Ucn1和Ucn2的稳态分布体积相似（8 L），但Ucn3的稳态分布体积明显大于Ucn3 （23.5 L）。两室模型充分描述了Ucn1的分布，而Ucn2和Ucn3则需要一室模型。Ucn1的半衰期分别为2.9 h （a相）和8.3 h （β相），Ucn2和Ucn3的半衰期分别为15.7和4.4 min。所有Ucns均显著增加心率、心输出量、左室收缩压和平均动脉压，降低左房压和外周阻力。延迟效应药效学模型最好地描述了血流动力学反应的时间过程，与Ucn1相比，Ucn2和Ucn3的作用更快，持续时间更短。所有ucn均表现出相似且生理上合理的估计基线（E0）效应，而Ucn1的EC50值通常更高。结论和意义相对于Ucn1， Ucn2和Ucn3的PK和血流动力学反应发生得更快。我们的数据提供了重要的比较信息，有助于今后临床研究的合理设计。
BACKGROUND AND PURPOSE The urocortin (Ucn) peptides are emerging as potential therapeutic targets for heart disease. However, pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking. Therefore, we investigated the PK/PD for all three Ucns. EXPERIMENTAL APPROACH Seven sheep received 1 mu g center dot kg-1 boluses of Ucn1, Ucn2 and Ucn3. Population PK/PD models were developed to describe the time course of the haemodynamic effects. RESULTS The population estimate for Ucn1 clearance (0.486 L center dot h-1) was lower than that for Ucn2 (21.7 L center dot h-1) and Ucn3 (220 L center dot h-1), while steady-state volumes of distribution were similar for Ucn1 and Ucn2 (similar to 8 L) but substantially larger for Ucn3 (23.5 L). Ucn1 disposition was adequately described by a two-compartment model, with a one-compartment model required for Ucn2 and Ucn3. The half-life for Ucn1 was 2.9 h (a phase) and 8.3 h (beta phase), and 15.7 and 4.4 min for Ucn2 and Ucn3 respectively. All Ucns produced significant increases in heart rate, cardiac output and left ventricular systolic and mean arterial pressures, and decreases in left atrial pressure and peripheral resistance. Delayed-effect pharmacodynamic models best described the time course of haemodynamic responses, with effects more rapid and less prolonged for Ucn2 and Ucn3 than Ucn1. Similar and physiologically plausible estimated baseline (E0) effects were exhibited by all Ucns, whereas EC50 values were generally greater for Ucn1. CONCLUSIONS AND IMPLICATIONS Relative to Ucn1, both the PK and haemodynamic responses to Ucn2 and Ucn3 occurred more rapidly. Our data provide important comparative information, useful to the rational design of future clinical studies.