Intra-arterial infusions of drugs and hyperosmotic solutions as ways of enhancing CNS chemotherapy

Abstract

The use of intra-arterial (ia) infusions of drugs to enhance their target tissue uptake and minimize their systemic delivery and toxicity was examined by mathematical analysis and computer modeling. In addition, the effects of intracarotid infusions of hyperosmotic solutions on blood-brain barrier permeability and the transfer of solutes between blood and CNS were evaluated with rats. In virtually all situations, at least some increased target site drug delivery and decreased systemic drug distribution will be obtained by an ia infusion. Significant ia infusion advantages for the target tissue will be realized in situations where either the rate of blood flow through the infused artery and the associated capillary bed within the target site is very low or the rate of systemic drug transformation or excretion is very high. If the drug's rate of transformation-excretion within the target tissue is appreciable, factors that produce a long residence or transit time for these molecules within the target site, namely low blood flow, high capillary permeability, and large distribution space, will decrease systemic drug delivery with an ia infusion. The study of blood-brain barrier (BBB) opening by ia hyperosmotic infusion indicated that BBB permeability is increased 30 to 50-fold in various brain areas over short periods of time (less than 6 minutes) and returns to normal over the next hour or so with this technique in the rat. Clear regional and subregional variations in opening were also observed.