Paclitaxel-induced arterial wall toxicity and inflammation: tissue uptake in various dose densities in a minipig model.
OBJECTIVE
Paclitaxel is an antiproliferative agent in drug-eluting stents with largely unknown tissue interaction. Toxicity might result from overdosage and/or accumulation. Part 1 of this two-step study investigated how paclitaxel uptake depends on dose density, coronary drug transfer kinetics, and elution efficacy.


METHODS
With cobalt chromium stents and Polyzene-F nanoscale coating, low, intermediate, and high paclitaxel dose densities (25 microg, 50 microg, and 150 microg per stent) were investigated in porcine right coronary arteries (RCAs). Coronary and myocardial tissue concentration measurements and determination of on-stent paclitaxel and plasma concentrations were performed at 2, 8, 24, and 72 hours.


RESULTS
For all stents, uptake was similar at all time intervals (paclitaxel RCA concentration range, 1,610-33,300 ng). Low- and intermediate-dose stents showed similar RCA concentrations, but those for high-dose stents were three times greater. Residual on-stent paclitaxel concentration was not time-dependent, at 33.3% on low-, 30.6% on intermediate-, and 17.4% on high-dose stents. Paclitaxel was measurable in only the plasma immediately after stent placement, with a linear dose relationship and a timely regression: measurements in high-dose stents were 0.0454-0.656 ng/mL at 1 minute and 0.0329-0.0879 ng/mL at 5 minutes. Untreated control samples of the left coronary artery showed a linear dose-dependent concentration (12.6 ng/g, 21.2 ng/g, and 85.2 ng/g).


CONCLUSIONS
Overall coronary paclitaxel uptake is fairly independent from the baseline overall dose density and, hence, depends on immediate binding mechanisms of the arterial wall. This is supported by the fact that, regardless of the applied dose density, the kinetics of paclitaxel uptake did not follow an exposure time pattern.
Radeleff
Boris
B
Department of Radiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Lopez-Benitez
Ruben
R
Stampfl
Ulrike
U
Stampfl
Sibylle
S
Sommer
Christof
C
Thierjung
Heidi
H
Berger
Irina
I
Kauffmann
Guenter
G
Richter
Goetz M
GM
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D002858:Chromium Alloys; D020099:Coated Materials, Biocompatible; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011108:Polymers; D011474:Prosthesis Design; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
D002317:Cardiovascular Agents; D002858:Chromium Alloys; D020099:Coated Materials, Biocompatible; D011108:Polymers; D017239:Paclitaxel