Arterial paclitaxel distribution and deposition

Successful implementation of local arterial drug delivery requires transmur al distribution of drug. The physicochemical properties of the applied comp ound, which govern its transport and tissue binding, become as important as the mode of delivery. Hydrophilic compounds distribute freely but are clea red rapidly. Hydrophobic drugs, insoluble in aqueous solutions, bind to fix ed tissue elements, potentially prolonging tissue residence and biological effect. Paclitaxel is such a hydrophobic compound, with tremendous therapeu tic potential against proliferative vascular disease. We hypothesized that the recent favorable preclinical data with this compound may derive in part from preferential tissue binding as a result of unique physicochemical pro perties. The arterial transport of paclitaxel was quantified through applic ation ex vivo and measurement of the subsequent transmural distribution. Ar terial paclitaxel deposition at equilibrium varied across the arterial wall and was everywhere greater in concentration than in the applied drug sourc e. Permeation into the wall increased with time, from 15 minutes to 4 hours , and varied with the origin of delivery. In contrast to hydrophilic compou nds, the concentration in tissue exceeds the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and periva scular paclitaxel application led to markedly differential deposition acros s the blood vessel wall. These data suggest that paclitaxel interacts with arterial tissue elements as it moves under the forces of diffusion and conv ection and can establish substantial partitioning and spatial gradients acr oss the tissue. The complexity of paclitaxel pharmacokinetics requires in-d epth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.