Shimada S, Nakajima Y, Yamamoto K, Sawada Y, Iga T
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Biol Pharm Bull. 1996 Mar;19(3):430-7. doi: 10.1248/bpb.19.430.
The relationships between plasma drug concentration and antihypertensive effect of eight calcium channel antagonists (nicardipine, nifedipine, nilvadipine, benidipine, manidipine, barnidipine, nitrendipine and efonidipine) in Japanese essential hypertensive patients were analyzed. Based on the effect compartment model, we could explain the long duration of the pharmacological effect, and there was significant correlation (r = 0.876, p < 0.05) between estimated EC50 values and the dissociation constants (Kd) obtained from in vitro binding studies. We also developed the ion-channel binding model to understand the pharmacodynamics of long acting calcium antagonists. The model was also well fitted to antihypertensive effect data. A significant correlation between the apparent in vivo dissociation constants and in vitro Kd values was observed with a slope of 1.45 (r = 0.913), suggesting that the mechanism of long-lasting antihypertensive effect of newer developed calcium antagonists is due to their high binding affinity at ion-channel sites.
分析了8种钙通道拮抗剂（尼卡地平、硝苯地平、尼伐地平、贝尼地平、马尼地平、巴尼地平、尼群地平和依福地平）在日本原发性高血压患者中的血浆药物浓度与降压效果之间的关系。基于效应室模型，我们可以解释药理作用的持续时间较长，并且从体外结合研究获得的估计EC50值与解离常数（Kd）之间存在显著相关性（r = 0.876，p < 0.05）。我们还开发了离子通道结合模型来理解长效钙拮抗剂的药效学。该模型也与降压效果数据拟合良好。观察到表观体内解离常数与体外Kd值之间存在显著相关性，斜率为1.45（r = 0.913），这表明新开发的钙拮抗剂长效降压作用的机制是由于它们在离子通道位点具有高结合亲和力。
