The Impact of Models, Drug Formulations, and Chemical Structure on the Intestinal Bioavailability of Protease Inhibitors
Norman, Devin O.
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The clinical development of peptides as therapeutic agents is a very important area of biological research today as peptidic drugs may effectively aid in the treatment of many chronic illnesses. Current attention is focused on the development of HIV protease inhibitors. The studies reported herein investigated the bioavailability of both peptidic and non-peptidic HIV protease inhibitors. Different animal models and drug formulations were employed to determine the effects of each on compound bioavailability. The first study evaluated the validity of the mesenteric vein intestinal perfusion model, an in situ system useful because it allows for the calculation of intestinal permeability coefficients. Unfortunately, the model was not found to be an accurate 'predictor of peptide bioavailability due to it's inability to achieve steady-state absorption levels. It was therefore necessary to utilize an in vivo model for the duration of this research. The second study involved the use of novel drug formulation techniques in hopes of enhancing peptide bioavailability. It has been theorized that oil formulations aid absorption by facilitating peptide transport across the lipid bilayer. These experiments utilized a digestion-resistant renin inhibitor, U-77436, and results indicated that no absolute advantage could be linked to oil formulations, as the oil and saline means were found to be statistically similar. Therefore, because peptides appear to have inherently poor bioavailability, a decision was made to concentrate on non-peptidic compounds. The intestinal bioavailability of a non-peptidic HIV protease inhibitor, NP-l, was found to be very high after ID dosing. If nonpeptides can be designed with inhibition activity in the nanomolar range, like the peptides, then these compounds could be developed for the treatment of AIDS.