Pharmacokinetic characterization of angiotensin IV analogs with therapeutic potential for cancer and dementia

Angiotensin IV is a peptide hormone that acts via the AT4 receptor with physiological functions that have not yet been fully elucidated but appear to include important roles in the processes of cognition, fluid balance, blood flow and vascular repair and remodeling. Angiotensin IV shares a partial homology with hepatocyte growth factor (HGF) and our laboratory has recently demonstrated that angiotensin IV analogs are able to effect changes in intracellular signaling cascades via the HGF receptor (c-Met). HGF/c-Met signaling is essential for embryonic development and is responsible for direction of cellular processes including differentiation, proliferation and migration. As the product of an oncogene, the c-Met receptor is also implicated to play a critical role cancer.Our laboratory has developed a library of angiotensin IV analogs with a number of these exhibiting strong potential as therapeutic agents for the treatment of cancer or dementia. Given that the failure of many therapeutic candidates in clinical trials can be attributed to unsuitable pharmacokinetics, our laboratory wished to establish a basic understanding of the pharmacokinetic characteristics of these molecules. We, therefore, set out to establish the basic pharmacokinetic profiles of three molecules, which serve as representative molecules for classes of chemical modifications to the angiotensin IV peptide made in our laboratory.This dissertation presents results from in-vitro and in-vivo studies describing pharmacokinetic characteristics for three angiotensin IV analogs in rats. These characteristics include measures of metabolic stability, clearance mechanisms and rates, and kinetic parameters, including half life, volume of distribution, and area under the concentration/time curve. These studies indicate strong potential as pharmaceutical candidates for some of our angiotensin IV analogs and a need for further chemical modification of others in order to overcome impractical pharmacokinetic characteristics. We additionally describe the development and validation of assays for quantification of these molecules in biological fluids.