Arterial Paclitaxel Distribution and Deposition

Abstract

Abstract-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.

Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel

“…The strong hydrophobic character of the drug can lead to high arterial wall concentrations that exceed the bulk concentration. 11 The resultant toxicity evidenced by inflammation and/or incomplete healing is most likely responsible for the lack of sustained suppression of neointimal growth with local delivery of PXL in animals.…”

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

“…The biological effects of a candidate drug are essential, but, ultimately, tissue residence time will determine effect and toxicity (6,7). Fueled by clinical relevance (8)(9)(10)(11), a number of studies have been carried out to detect, model, and predict the distribution of drugs within arterial segments beneath, adjacent to, and distant from stents (12)(13)(14)(15). Drugs that are retained within the blood vessel are far more effective than those that are not.…”

Systemic exposure of sirolimus after coronary stent implantation in patients with de novo coronary lesions: Supralimus-Core® pharmacokinetic study

“…Patients were excluded if any of the following conditions were present: General exclusion criteria: 1) Women of childbearing potential; 2) acute or chronic renal dysfunction (creatinine > 2.0 mg/dL or > 150 μmol/L); 3) any patient who has a platelet count < 100,000 cells/mm 3 or > 700,000 cells/mm 3 , a white blood cell of < 3000 cells/mm 3 ; 4) evidence of an acute Q-wave or non-Q-wave myocardial infarction within 72-hours preceding the index procedure; 5) restenotic or lesion in graft; 6) patient with a life expectancy less < 12 months; 7) known allergies to aspirin, clopidogrel bisulphate (Plavix ® ), ticlopidine (Ticlid ® ), heparin or cobalt chromium; 8) any significant medical condition which in the investigator's opinion may interfere with the patient's optimal participation in the study; 9) currently participating in an investigational drug, or another device study, or subject to inclusion in another investigational drug, or another device study during follow-up; 10) previous bare metal stenting (< 1 year) anywhere within the target vessel or previous DES anywhere within any epicardial vessel; and 11) any contraindication to blood sampling.…”

“…[1][2][3] A new type of metallic stent has been engineered specifically as a next-generation coronary drug delivery system that allows precise and programmable control over special and temporal release kinetics. Drug-eluting stents are widely used for the treatment of coronary artery disease (CAD) due to significant improvement in angiographic outcome, with reduced rates of restenosis and need for revascularisation compared with bare metal stents (BMS).…”