DOI
https://doi.org/10.25772/K2QZ-7186
Author ORCID Identifier
https://orcid.org/0000-0002-2318-5218
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Phillip Gerk
Abstract
This research project mainly focused on the development of preclinical approaches to enhance the oral bioavailability of a naturally occurring herbal supplement, ursolic acid (UA). The expected outcomes were verified in silico by comparing the observed human PK profiles of UA against the predicted PK profiles of optimized UA. The preclinical approaches mainly tackled the low solubility and extensive pre-systemic metabolism issues by formulating UA into a salt complex and blocking its pre-systemic metabolism using natural or dietary compounds, respectively. For solubility enhancement, several salt complex candidates were prepared and assessed on their physicochemical properties such as solid state, solubility, water content. Dicholine ursolate (UAdC-W) was found to be the optimal salt complex since it significantly improved UA aqueous solubility. It was further investigated regarding its biopharmaceutical properties, such as Log D, biorelevant solubility, stoichiometry. In terms of pre-systemic metabolism, UA and UAdC-W exhibited similar metabolic characteristics (pathways and rates) in the liver and intestine, respectively. The salt complex structure did not alter the metabolism of the parent molecule. Several natural or dietary molecules were found potent in inhibiting UA intestinal and/or hepatic metabolism in vitro. A PBPK model was built and validated based on experimental and observed human PK data, and it was applied for predicting oral PK of optimized UA. In silico prediction indicated that UA with dehydroepiandrosterone (DHEA) and UAdC with DHEA were able to increase Foral of UA substantially. Specifically, at a dose of 40 mg, UA with DHEA and UAdC with DHEA were predicted to increase Foral from 4% to 53% and 68%, respectively; and from 3% to 38% and 65% at 80 mg, respectively. In addition, the inter-subject variabilities within the PK parameters were predicted to decrease drastically by those two combinations as opposed to UA. In conclusion, preclinical strategies of enhancing solubility and inhibiting first-pass metabolism were proved to be effective in improving oral systemic exposure and its variability for UA dietary products.
Rights
© Renjie Zhan
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2023