DOI
https://doi.org/10.25772/13WT-SY98
Author ORCID Identifier
https://orcid.org/0000-0003-4394-3570
Defense Date
2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Phillip M. Gerk
Abstract
This dissertation research aimed to determine the preclinical pharmacokinetics of pterostilbene in vitro and develop a physiologically based pharmacokinetic (PBPK) model to simulate the animal and human PK profiles for pterostilbene. The in vitro PK characteristics of pterostilbene, including Caco-2 cell permeability, plasma protein binding, and metabolic stability were determined using rat and human intestinal & hepatic S9 subcellular fractions. The in vitro metabolic parameters determined in rat subcellular fractions were extrapolated to in vivo values to predict the oral bioavailability (Foral) in rats. The predicted Foral was found to be 43.0 %, which is similar to what has been observed in vivo (35 – 59 %). The human in vitro metabolic parameters were extrapolated using IVIVE, and the fractions available of PT in the intestine and liver were predicted to be 13 % and 72 %, respectively. In the intestine, glucuronidation appeared to be the major metabolic pathway with almost 3-fold higher intrinsic clearance than sulfation, while the intrinsic clearances of both the pathways in the liver were similar. Pterostilbene was predicted to show a Foral of 9.60 % in humans. Pterostilbene has previously been shown to be an effective inhibitor of the presystemic metabolism of buprenorphine and improve its oral bioavailability. Thus, the lower Foral of pterostilbene would be beneficial for its application as an enzyme inhibitor. The physiologically based pharmacokinetic model was built using GastroPlus and used to simulate PK profiles in both rats and humans based on the in vitro determined parameters. The predicted PK parameters such as Cmax, AUC0-∞, and steady-state volume of distribution were within the 2-fold error margin of the observed values in rats. This validated model was then used to predict the PK profiles in humans after IV and oral administration of pterostilbene. This developed PBPK model can prove useful in predicting pterostilbene oral absorption and bioavailability in humans and serve as the basis for planning future clinical study designs.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-12-2021