van der Lee R, Pfaffendorf M, van Zwieten P A
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands.
J Hypertens. 2000 Nov;18(11):1677-82. doi: 10.1097/00004872-200018110-00021.
To investigate a possible relationship between the time courses of action of various calcium antagonists and their lipophilicity, characterized as log P-values.
The functional experiments were performed in vitro in human small subcutaneous arteries (internal diameter 591 +/- 51 microm, n = 7 for each concentration), obtained from cosmetic surgery (mamma reduction and abdominoplasty). The vessels were investigated in an isometric wire myograph. The vasodilator effect of the calcium antagonists was quantified by means of log IC50-values, and the onset of the vasodilator effect for each concentration studied was expressed as time to Eeq90-values (time to reach 90% of the maximal effect).
Log IC50-values were -8.46 +/- 0.09, -8.33 +/- 0.25 and -8.72 +/- 0.16 for nifedipine, felodipine and (S)-lercanidipine, respectively (not significant). On average, nifedipine reached time to Eeq90 in 11 +/- 1 min. For felodipine and (S)-lercanidipine the corresponding values were 60 +/- 11 min and 99 +/- 9 min, respectively. The differences between these values were statistically significant (P< 0.01). In spite of these differences in the in-vitro human vascular model, the three calcium antagonists are equipotent with regard to their vasodilator effects. Linear regression analysis of the correlation between the logarithm of the membrane partition coefficient (log P-values) of the calcium antagonists tested [2.50, 4.46 and 6.88 for nifedipine, felodipine and (S)-lercanidipine, respectively] and their respective values found for time to Eeq90 was highly significant.
It appears that a higher log P-value is correlated with a slower onset of action.
研究各种钙拮抗剂的作用时程与其脂溶性（以log P值表示）之间可能存在的关系。
功能性实验在体外对取自整形手术（乳房缩小术和腹部整形术）的人皮下小动脉（内径591±51微米，每种浓度n = 7）进行。血管在等长线肌动描记器中进行研究。钙拮抗剂的血管舒张作用通过log IC50值进行量化，每种研究浓度的血管舒张作用起效时间表示为达到Eeq90值的时间（达到最大效应的90%的时间）。
硝苯地平、非洛地平和(S)-乐卡地平的log IC50值分别为-8.46±0.09、-8.33±0.25和-8.72±0.16（无显著差异）。平均而言，硝苯地平达到Eeq90的时间为11±1分钟。非洛地平和(S)-乐卡地平的相应值分别为60±11分钟和99±9分钟。这些值之间的差异具有统计学意义（P<0.01）。尽管在体外人体血管模型中存在这些差异，但三种钙拮抗剂在血管舒张作用方面是等效的。对所测试的钙拮抗剂的膜分配系数对数（log P值）[硝苯地平、非洛地平和(S)-乐卡地平分别为2.50、4.46和6.88]与其各自的Eeq90时间值之间的相关性进行线性回归分析，结果高度显著。
似乎log P值越高，起效越慢。
