Arterial paclitaxel distribution and deposition.
Successful implementation of local arterial drug delivery requires transmural distribution of drug. The physicochemical properties of the applied compound, which govern its transport and tissue binding, become as important as the mode of delivery. Hydrophilic compounds distribute freely but are cleared rapidly. Hydrophobic drugs, insoluble in aqueous solutions, bind to fixed tissue elements, potentially prolonging tissue residence and biological effect. Paclitaxel is such a hydrophobic compound, with tremendous therapeutic 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 properties. The arterial transport of paclitaxel was quantified through application ex vivo and measurement of the subsequent transmural distribution. Arterial paclitaxel deposition at equilibrium varied across the arterial wall and was everywhere greater in concentration than in the applied drug source. Permeation into the wall increased with time, from 15 minutes to 4 hours, and varied with the origin of delivery. In contrast to hydrophilic compounds, the concentration in tissue exceeds the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and perivascular paclitaxel application led to markedly differential deposition across the blood vessel wall. These data suggest that paclitaxel interacts with arterial tissue elements as it moves under the forces of diffusion and convection and can establish substantial partitioning and spatial gradients across the tissue. The complexity of paclitaxel pharmacokinetics requires in-depth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.
Creel
C J
CJ
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Lovich
M A
MA
Edelman
E R
ER
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D016503:Drug Delivery Systems; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D014652:Vascular Diseases / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D017239:Paclitaxel