Giacometti A, Micheli D, Gaviraghi G, Trist D G
Glaxo Research Laboratories, Verona, Italy.
J Pharmacol Exp Ther. 1994 Apr;269(1):424-9.
The calcium antagonist activity of the long-acting 1,4-dihydropyridine (DHP) lacidipine has been analyzed in rabbit basilar artery using a washout design in constant depolarizing conditions. From the kinetics of the loss of effect with washing, it was possible to fit a model that included the rate constant for dissociation of the DHP from the membrane (k-1) together with its affinity for the voltage-activated channel (K2). The k-1 values for lacidipine and two other DHPs (amlodipine and nifedipine) have been calculated as 0.0098, 0.0182 and 0.166 min-1, respectively. Assuming that the externally applied concentration of the DHP reflected the concentration in the membrane, the apparent pK2 values of 9.80, 9.0 and 9.25 were calculated for the three calcium antagonists. These values are in good agreement with those estimated in a previous study. When the partition of lacidipine into the membrane was taken into consideration, its apparent pK2 was reduced to 4.85. Thus, the study reinforces the concept that the high membrane partition of lacidipine contributes not only to its duration of action but also to its very high potency.
长效1,4 - 二氢吡啶（DHP）拉西地平的钙拮抗剂活性已在兔基底动脉中采用恒流去极化条件下的洗脱设计进行了分析。根据洗脱时效应丧失的动力学，有可能拟合一个模型，该模型包括DHP从膜上解离的速率常数（k-1）及其对电压激活通道的亲和力（K2）。拉西地平和另外两种DHP（氨氯地平和硝苯地平）的k-1值分别计算为0.0098、0.0182和0.166 min-1。假设外部施加的DHP浓度反映了膜中的浓度，则计算出这三种钙拮抗剂的表观pK2值分别为9.80、9.0和9.25。这些值与先前研究中估计的值高度一致。当考虑拉西地平在膜中的分配时，其表观pK2降至4.85。因此，该研究强化了这样一个概念，即拉西地平的高膜分配不仅有助于其作用持续时间，也有助于其非常高的效力。
