Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxel.
The growing use of local drug delivery to vascular tissues has increased interest in hydrophobic compounds. The binding of these drugs to serum proteins raises their levels in solution, but hinders their distribution through tissues. Inside the arterial interstitium, viscous and steric forces and binding interactions impede drug motion. As such, this might be the ideal scenario for increasing the amount of drug delivered to, and residence time within, arterial tissues. We quantified carrier-mediated transport for paclitaxel, a model hydrophobic agent with potential use in proliferative vascular diseases, by determining, in the presence or absence of carrier proteins, the maximum concentration of drug in aqueous solution, the diffusivity in free solution, and the diffusivity in arterial tissues. Whereas solubility of paclitaxel was raised 8.1-, 21-, and 57-fold by physiologic levels of alpha(1)-acid glycoproteins, bovine serum albumin, and calf serum over that in protein-free solution, diffusivity of paclitaxel in free solution was reduced by 41, 49, and 74%, respectively. When paclitaxel mixed in these solutions was applied to arteries both in vitro and in vivo, drug was more abundant at the tissue interface, but protein carriers tended to retain drug in the lumen. Once within the tissue, these proteins did not affect the rate at which drug traverses the tissue because this hydrophobic drug interacted with the abundant fixed proteins and binding sites. The protein binding properties of hydrophobic compounds allow for beneficial effects on transvascular transport, deposition, and distribution, and may enable prolonged effect and rationally guide local and systemic strategies for their administration.
Lovich
M A
MA
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room 16-343, Cambridge, MA 02139, USA.
Creel
C
C
Hong
K
K
Hwang
C W
CW
Edelman
E R
ER
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D004058:Diffusion; D017239:Paclitaxel / Q000493:pharmacokinetics*; D012996:Solutions
D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D012996:Solutions; D017239:Paclitaxel