Ma. Lovich et Er. Edelman, Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo, P NAS US, 96(20), 1999, pp. 11111-11116
Citations number
27
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Drug activity is often studied in well controlled and characterized cellula
r 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 resp
onse to drugs in vivo have been limited by the inability to reliably determ
ine or predict the concentrations achieved in tissues. We developed a metho
d to study the dose response of injured arteries to exogenous heparin in vi
vo 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. W
e predicted the distribution of heparin throughout the arterial wall by usi
ng computational simulations of intravascular drug binding and transport, a
nd we correlated these concentrations with the biologic response of the tis
sues. This allowed the estimation of the arterial concentration of heparin
required to maximally inhibit intimal hyperplasia after injury in vivo, 0.3
mg/ml. This estimation of the required concentration of drug seen by a spe
cific tissue is independent of the route of administration and holds for al
l forms of drug release. In this way we may now be able to evaluate the pot
ential 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.