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.
Local vascular drug delivery systems provide elevated concentrations in target arterial tissues, while minimizing systemic side effects. Drug can now be released to isolated arterial segments from the endovascular or perivascular aspects of the blood vessel, yet the forces that determine drug distribution and deposition for these different modes of delivery have not been rigorously investigated. This study examines mechanisms of transmural transport of a model vasoactive drug, heparin, and compares estimates of the distribution after administration from either aspect of the artery. We showed that (1) heparin traversed the arterial wall rapidly; (2) diffusion far outweighed convection in the control of transmural heparin transport in the normal artery, but after endothelial injury, convective forces rose to one quarter the magnitude of diffusive forces; (3) the endothelium posed a minimal diffusive barrier to heparin; and (4) the diffusive barrier imposed by the adventitia depended on its thickness. These findings strongly suggest that vasoregulatory compounds can be administered to target tissue by either perivascular or endovascular means with equal efficacy, because the forces governing transport of heparin from either aspect of the blood vessel wall are not significantly different. Furthermore, the differences in arterial transport properties between heparin and other macromolecules suggest that distribution and the optimal aspect of delivery will depend just as much on the physicochemical properties of the drug as the state of the blood vessel wall.
The dynamics of IV drug delivery resulting from drug infusions connected to main-line crystalloid carriers can be complex and depend on infusion set dead-volume, drug flow rate, and carrier flow rate. While the concept of dead-volume is intuitive, a lack of appreciation of the interaction with the carrier and drug flow rates can lead to unintended clinical effects resulting from large variations in the delivery rate of potent drugs. We derived mathematical models to quantify these interactions. Experimental simulation with methylene blue infusions tested these predictions. The models predict a lag in response time to changes in carrier or drug flow, which is proportional to the dead-volume and inversely related to the total flow rate. Increasing the carrier rate provides an acute drug bolus. Temporary reduction or cessation of carrier flow decreases the rate of drug delivery, potentially for prolonged periods. Furthermore, a drug bolus results from restoration of the carrier flow. The method of connecting an infusion to a carrier and the use history affects the dynamics of drug delivery. Thus, although complex, the impact of infusion set architecture and changes in carrier and drug flow rates are predictable. These quantitative studies may help optimize the safe use of IV drug infusion systems.
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.
Transvascular transport has been studied with atherogenic, tracer, and inert compounds such as low-density lipoprotein, horseradish peroxidase, and albumin, respectively. Few studies used vasoactive compounds, and virtually all studies examined entry from the lumen and not from the perivascular space. We compared several mechanisms that govern arterial heparin deposition after administration to the perivascular and endovascular aspects of the calf carotid artery in vitro and the rabbit iliac artery in vivo. In the absence of transmural hydrostatic pressure gradients, heparin deposition following endovascular administration was unaffected by deendothelialization and was indistinguishable from perivascular delivery. Deposition in the former was enhanced by the addition of a pressure gradient and to a greater extent in denuded arteries, indicating that convection influences transport but is dampened by the endothelium. Neither the endothelium nor the adventitia pose significant resistances to heparin. Deposition in vivo was greater following endovascular hydrogel release than perivascular application from similar devices to native or denuded arteries. The loss of drug to extra-arterial microvessels exceeded the loss of drug to the lumen flow. These findings are essential for describing vascular pharmacokinetics and for implementing local pharmacotherapies.
IV drug infusion has the potential for dosing errors, which arise from complex interactions between carrier flows and the infusion set dead volume. We computed the steady-state mass of drug stored in the infusion set dead volume, using phenylephrine as a model compound. The mass of drug in the dead volume increases with stock drug concentration and desired dose but decreases with carrier flow rate. We also modeled the dynamic perturbations in drug delivery when a carrier is abruptly stopped. Rapid initial carrier flow rates lead to greater depression in drug delivery rate after carrier flow ceases. Rapid drug infusion rates lead to faster restoration of desired drug delivery. Finally, the time to reach a new steady-state after a change in drug delivery or carrier rate was computed. This time is longest for large stock-drug concentrations, larger dead volumes, and slower final carrier rates. These computations illustrate that (a) the dead volume may contain a large mass of drug available for inadvertent bolus, (b) cessation of carrier flow can profoundly reduce drug delivery, and (c) after a change in carrier flow or drug dosing, a significant lag is possible before drug delivery achieves steady state. Although computed for phenylephrine, the concepts are generic and valid for any drug administered by IV infusion.
Drug activity is often studied in well controlled and characterized cellular environments in vitro. However, the biology of cells in culture is only a part of the tissue behavior in vivo. Quantitative studies of the dose response to drugs in vivo have been limited by the inability to reliably determine or predict the concentrations achieved in tissues. We developed a method to study the dose response of injured arteries to exogenous heparin in vivo by providing steady and predictable arterial levels of drug. Controlled-release devices were fabricated to direct heparin uniformly and at a steady rate to the adventitial surface of balloon-injured rat carotid arteries. We predicted the distribution of heparin throughout the arterial wall by using computational simulations of intravascular drug binding and transport, and we correlated these concentrations with the biologic response of the tissues. This allowed the estimation of the arterial concentration of heparin required to maximally inhibit intimal hyperplasia after injury in vivo, 0.3 mg͞ml. This estimation of the required concentration of drug seen by a specific tissue is independent of the route of administration and holds for all forms of drug release. In this way we may now be able to evaluate the potential of widely disparate forms of drug release and to finally create some rigorous criteria by which to guide the development of particular delivery strategies for local diseases.
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