While, local drug delivery has been touted as an exciting therapeutic option for many diseases, including cardiovascular pathologies, this theoretical promise and the excitement of preliminary animal studies has not been realized in the clinic. The first phase of R01 support helped us realize that: 1) local administration is not synonymous with local delivery, 2) we do not yet fully understand the potential benefits, limitations and mechanisms of local delivery, and 3) pharmacological tools that define and characterize systemic administration do not fully describe events when drugs are applied directly to specific segments of the vessel wall. We have shown that the deposition and distribution of drug in the arterial wall following local delivery to be complex and dependent upon intramural transport and binding processes. We developed a rigorous framework by which to characterize local vascular pharmacokinetics, and illustrated our ability to predict drug deposition and distribution with high resolution, using a model vasotherapeutic compound, heparin. At the same time, we have shown how the complexity of the regulation of the biologic target (e.g. cell cycle oncogenes and growth factor receptors) modulates a drug's biologic effect. Thus, the success of any local delivery strategy depends on matching the kinetics of drug release to the mechanisms of drug deposition and distribution in the target tissues, and the temporal sequence of target lesion pathology. We hope to examine the biology and enhance the clinical utility of local vascular delivery systems by validating and extending our local vascular pharmacokinetic analyses to higher animal species, more sophisticated arterial architectures, altered states and complex arterial lesions, and drugs of different physicochemical properties. Understanding where drugs distribute and are deposited in detail might not only ensure adequate drug kinetics to achieve biologic effect, but will also enable study of specific agents in more applicable and complete models of disease. We therefore now seek to: . determine if vascular pharmacokinetic models predict spatial distribution of drug within the arterial wall. . ascribe a structural and anatomic basis for the transport and deposition we have observed. . correlate pharmacokinetic parameters with solute chemical properties crucial to solute transport, and . examine how altered vascular states influence pharmacokinetics, drug deposition and biologic effects.
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