Drug clearance and arterial uptake after local perivascular delivery to the rat carotid artery

Abstract

Objectives: We attempted to characterize how drug released into the perivascular space enters the arterial wall and how it is cleared from the local environment.

Background: Drug released into the perivascular space can enter the artery either from the adventitial aspect or from the lumen after absorption by the extraarterial capillaries and mixing within the systemic circulation. Some investigators suggest that this latter mechanism dominates, and they question whether local drug release is synonymous with local deposition.

Methods: We investigated both the pathways by which adventitially released drug is cleared from the perivascular space and those by which drug enters the blood vessel wall. Inulin was used to follow drug release from implanted devices and subsequent entry to the circulation, because of its first-pass urinary excretion. Heparin was used to follow arterial deposition because of its vasoactivity and tissue-binding properties. The different potential pathways of drug entry and egress were systematically removed and the effects on metabolism and deposition determined.

Results: Ligature occlusion of the artery did not decrease inulin excretion or heparin deposition. Extravascular wraps designed to shield the device from extramural capillaries reduced inulin excretion rates 10-fold but did not alter heparin deposition into the vessel wall. The deposition of drug after perivascular delivery was 500 times higher than after intraperitoneal administration.

Conclusions: Although almost all the drug released into the perivascular space is cleared through the extravascular capillaries, virtually all the deposited drug diffuses directly from the perivascular space, and little arrives from the endovascular aspect. These data support the view that local drug release leads directly to increased local drug concentration.