Computational simulations of local vascular heparin deposition and distribution.
Local vascular drug delivery systems provide elevated concentrations in target arterial tissues while minimizing systemic side effects; however, definition of their precise pharmacokinetics remains elusive. The standard labeled tracer assays used in experimental vascular pharmacokinetic studies of these systems are limited because they quantify the arterial average drug concentration as opposed to transmural concentration profiles, require many animal experiments to elucidate the time-varying deposition, and track label rather than intact biologically active drug. In this study, computational simulations of drug deposition and distribution in vascular tissues after release from these systems have provided two important insights. First, simulations of arteries that were uniformly loaded with heparin predicted that most of the drug is cleared in < 1 h, illustrating the need for sustained modes of delivery. Second, some of the limitations of labeled tracers can be over come by combining experimental data with simulations that provided high spatial resolution. This enabled us to describe the kinetics of the deposited drug and distinguish soluble from reversibly bound and internalized drug within cells. The latter can help differentiate biologically viable drug from its committed inactive form or metabolites. These points have been illustrated through simulations of a novel endovascular hydrogel heparin-delivery system that has been applied to the porcine coronary artery. The basic models used in these simulations are generalized, and with the appropriate boundary conditions, binding and distribution constants can be used to study the physical interactions between any compound and tissue.
Lovich
M A
MA
Division of Health Sciences and Technology, Harvard University-Massachusetts Institute of Technology, Cambridge 02139, USA.
Edelman
E R
ER
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D003198:Computer Simulation; D003331:Coronary Vessels / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D011092:Polyethylene Glycols; D013552:Swine; D014018:Tissue Distribution
D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D006493:Heparin