Lesion complexity determines arterial drug distribution after local drug delivery.
Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels. We correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits with lesions induced by dietary manipulation and controlled injury. Paclitaxel, everolimus, and sirolimus depositions in the human aortae were maximal in the media and scaled inversely with lipid content. Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated a differential transmural deposition pattern that was amplified with disease and correlated with the expression of their intracellular targets, tubulin and FKBP-12. Tubulin distribution and paclitaxel binding increased with vascular injury and macrophage infiltration, and were reduced with lipid content. Sirolimus analogs and their specific binding target FKBP-12 were less sensitive to alterations of diet in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury. The data demonstrate that disease-induced changes in the distribution of drug-binding proteins and interstitial lipid alter the distribution of these drugs, forcing one to consider how disease might affect the evaluation and efficacy of the local release of these and like compounds.
Tzafriri
Abraham R
AR
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ramitz@mit.edu
Vukmirovic
Neda
N
Kolachalama
Vijaya B
VB
Astafieva
Irina
I
Edelman
Elazer R
ER
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D054855:Drug-Eluting Stents; D000068338:Everolimus; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*
D002784:Cholesterol; D000068338:Everolimus; D017239:Paclitaxel; D020123:Sirolimus