Androgen receptor antagonists QUER demonstrated reduced binding avidity for plasma proteins, potentially limiting the tissue residence time of QUER. In studies of drug diffusion across a porous membrane, the presence of protein significantly limited the diffusion of Taxol and RESV. These data for Taxol corroborate earlier studies,4 suggesting that diffusion of drugs featuring high protein binding hinders drug velocity through tissue. Consistent with limited protein binding, QUER reached steady state in arterial tissue significantly faster than Taxol or RESV. To further elucidate these arterial dynamics, a pharmacokinetic tissue loading profile was determined in segments of bovine carotid artery. At equilibrium, the lipophilic compounds deposited into the tissue 50 fold to 60 fold higher than the applied drug concentration, whereas QUER partitioned only twofold. Consistent with protein binding interactions having strong influence on tissue partitioning,18 previous studies have shown that Taxol demonstrates specific binding to microtubules, providing a large drug bcl-2 sink within the vessel wall.20 Additionally, Taxol has been shown to accumulate in arterial regions of high elastin content, suggesting that elastin is a nonspecific binding substrate for Taxol.
Given that albumin serves as a protein carrier for RESV, and albumin has high affinity for elastin,45 the partitioning of RESV in arterial tissue may be driven by an association between RESV bound albumin and networks of elastin fibers. However, TNF-Alpha signaling pathway studies are required to clarify the specific binding interactions that are responsible for sequestering RESV within the arterial wall. Similar to published transmural and planar arterial diffusivity, diffusion of Taxol was found to be approximately 10× faster in the planar direction compared with transmural diffusion.20 Anisotropic diffusion was also observed for RESV and QUER. These results suggest that once these drugs enter the tissue compartment, they preferentially move parallel to the arterial wall layers, following the path of least resistance.18 It is possible that elastin fibers, which form discrete concentric layers within the arterial wall, have influence on this anisotropic diffusionby creating a barrier to movement in the transmural direction. The contribution of protein binding on ZD6474 arterial diffusion was estimated by comparing calculated diffusion coefficients including tissue binding capacity, with the theoretical situation, assuming k 1.
The results show that protein binding significantly contributes to slowing the arterial diffusion of Taxol and RESV, but not QUER, and most likely contributes to the robust arterial partitioning of RESV relative to QUER. A caveat of these studies is that arterial transport was studied using healthy porcine arteries. It is possible that drug kinetics may be altered in vessels containing atherosclerotic plaques.46 The 2D computational model utilized a dual layer polymer compartment to account for the complex chemical interactions of the drugs with the polymer matrix that result in a biphasic release profile. External validation of the proposed model demonstrated that the simulation showed good agreement with an experimental drug release profile from a clinically available DES. Notable differences in predicted drug release.