Lilleberg J, Antila S, Karlsson M, Nieminen M S, Pentkäinen P J
First Department of Medicine, University of Helsinki, Finland.
Clin Pharmacol Ther. 1994 Nov;56(5):554-63. doi: 10.1038/clpt.1994.177.
To assess pharmacokinetics and correlation of pharmacokinetics and pharmacodynamics of simendan, a new calcium-sensitizing compound aimed at the treatment of congestive heart failure, in healthy volunteers.
Simendan was administered to eight healthy subjects in seven different doses, and its concentrations in plasma and proportions of enantiomers (levosimendan and dextrosimendan) were determined. Hemodynamic effects were measured by M-mode echocardiography.
The area under the plasma concentration time-curve increased linearly and correlated with dose (p < 0.001). The volumes of distribution were small (mean VC, 8.5 to 14.1 L; VSS, 12.8 to 28.4 L) and elimination fairly fast (mean t1/2 beta, 0.83 to 1.77 hours). There were only minor differences between the pharmacokinetic profiles of the enantiomers of simendan. The increase in maximal ejection fraction (EF) correlated significantly with the plasma concentrations of simendan (p < 0.01; r2 = 0.33). However, the correlation coefficient was higher between estimated concentrations of simendan in peripheral compartment and ejection fraction; r2 was 0.79 (p < 0.01) and 0.94 (p < 0.001) after 2 and 5 mg doses, respectively. One subject after 5 mg simendan and one subject after 10 mg simendan had transient vasovagal reactions consisting of decreases in heart rate and blood pressure.
Simendan has favorable and predictable hemodynamic actions. The pharmacokinetic profile facilitates rapid dose adjustments during intravenous administration.
在健康志愿者中评估新型钙增敏化合物西孟旦（旨在治疗充血性心力衰竭）的药代动力学以及药代动力学与药效学的相关性。
对8名健康受试者给予7种不同剂量的西孟旦，并测定其血浆浓度和对映体（左西孟旦和右西孟旦）比例。通过M型超声心动图测量血流动力学效应。
血浆浓度-时间曲线下面积呈线性增加且与剂量相关（p < 0.001）。分布容积较小（平均VC，8.5至14.1 L；VSS，12.8至28.4 L），消除相当快（平均t1/2β，0.83至1.77小时）。西孟旦对映体的药代动力学特征之间仅有微小差异。最大射血分数（EF）的增加与西孟旦的血浆浓度显著相关（p < 0.01；r2 = 0.33）。然而，外周室中西孟旦的估计浓度与射血分数之间的相关系数更高；2 mg和5 mg剂量后r2分别为0.79（p < 0.01）和0.94（p < 0.001）。1名接受5 mg西孟旦的受试者和1名接受10 mg西孟旦的受试者出现了短暂的血管迷走反应，包括心率和血压下降。
西孟旦具有良好且可预测的血流动力学作用。药代动力学特征有利于静脉给药期间的快速剂量调整。
