The differential time courses of the vasodilator effects of various 1,4-dihydropyridines in isolated human small arteries are correlated to their lipophilicity.
OBJECTIVE
To investigate a possible relationship between the time courses of action of various calcium antagonists and their lipophilicity, characterized as log P-values.


METHODS
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).


RESULTS
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.


CONCLUSIONS
It appears that a higher log P-value is correlated with a slower onset of action.
van der Lee
R
R
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands. r.vdlee@amc.uva.nl
Pfaffendorf
M
M
van Zwieten
P A
PA
D000273:Adipose Tissue / Q000098:blood supply; D000293:Adolescent; D000328:Adult; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001940:Breast / Q000098:blood supply; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D016014:Linear Models; D008875:Middle Aged; D011930:Reaction Time; D012867:Skin / Q000098:blood supply*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine