Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxel

The growing use of local drug delivery to vascular tissues has increased in terest in hydrophobic compounds. The binding of these drugs to serum protei ns raises their levels in solution, but hinders their distribution through tissues. Inside the arterial interstitium, viscous and steric forces and bi nding interactions impede drug motion. As such, this might be the ideal sce nario for increasing the amount of drug delivered to, and residence time wi thin, arterial tissues. We quantified carrier-mediated transport for paclit axel, a model hydrophobic agent with potential use in proliferative vascula r 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 al pha (1)-acid glycoproteins, bovine serum albumin, and calf serum over that in protein-free solution, diffusivity of paclitaxel in free solution was re duced by 41, 49, and 74%, respectively. When paclitaxel mixed in these solu tions was applied to arteries both in vitro and in vivo, drug was more abun dant 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 pr operties of hydrophobic compounds allow for beneficial effects on transvasc ular transport, deposition, and distribution, and may enable prolonged effe ct and rationally guide local and systemic strategies for their administrat ion. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.