Physiological transport forces govern drug distribution for stent-based delivery

Background-The first compounds considered for stent-based delivery, such as heparin, were chosen on the basis of promising tissue culture and animal e xperiments, and yet they have failed to stop restenosis clinically. More re cent compounds, such as paclitaxel, are of a different sort, being hydropho bic in nature, and their effects after local release seem far more profound . This dichotomy raises the question of whether drugs that have an effect w hen released from a stent do so because of differences in biology or differ ences in physicochemical properties and targeting. Methods and Results-We applied continuum pharmacokinetics to examine the ef fects of transport forces and device geometry on the distribution of stent- delivered hydrophilic and hydrophobic drugs. We found that stent-based deli very invariably leads to large concentration gradients, with drug concentra tions ranging from nil to several times the mean tissue concentration over a few micrometers. Concentration variations were a function of the Peclet n umber (Pe), the ratio of convective to diffusive forces. Although hydrophob ic drugs exhibited greater variability than hydrophilic drugs, they achieve d higher mean concentrations and remained closer to the intima. Inhomogeneo us strut placement influenced hydrophilic drugs more negatively than hydrop hobic drugs, dramatically affecting local concentrations without changing m ean concentrations. Conclusions-Because local concentrations and gradients are inextricably lin ked to biological effect, our results provide a potential explanation for t he variable success of stent-based delivery. We conclude that mere proximit y of delivery devices to tissues does not ensure adequate targeting, becaus e physiological transport forces cause local concentrations to deviate sign ificantly from mean concentrations.