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Evaluating the Impact of Glycocalyx Partitioning of Basic Drugs and Developing a New Rat Physiologically Based Pharmacokinetic Model
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2025-08
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Pharmaceutical Sciences
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https://doi.org/10.34944/8ex7-w063
Abstract
A new rat permeability- and perfusion-limited physiologically based pharmacokinetic model, termed “Rat PermQ”, was developed to improve the prediction of intravenous drug concentration-time profiles and to evaluate distribution mechanisms. The model was built based on the previously established human PermQ framework and included an empirical protein binding factor special for acid drugs. Seven drugs, including acidic, neutral, and basic compounds, were evaluated by this model. In vitro plasma protein binding and blood-to-plasma ratio for atenolol, glyburide, and midazolam were collected in-house, and other in vitro ADME parameters and in vivo rat IV data were collected from the literature. A mechanistic hypothesis regarding the role of the endothelial glycocalyx in drug partitioning was also evaluated through in vitro experiments and the results were then integrated into the rat PermQ model. The rat PermQ model improved predictions of concentration-time profiles compared to conventional PBPK models. For acidic drugs, the prediction improved with the incorporation of active uptake and the empirical protein binding correction factor. For basic drugs, the addition of a shallow compartment significantly improved the predictions. After modifying the shallow compartment and applying in vitro partitioning data, the simulation results were comparable to those obtained using the original empirical method. Overall, the framework predicted C-t profiles of the tested drugs as well as or better than published PBPK models and can be used to evaluate different hypotheses in preclinical drug development.
Chapter One introduces the background concerning this project, along with the hypothesis and goals. Chapter Two presents the development and validation of bioanalytical methods for the drug of interest. Chapter Three involves in vitro ADME studies, including plasma protein binding and blood-to-plasma ratio. Chapter Four details the in vitro experiments used to evaluate the glycocalyx effect on drug partitioning. Chapter Five summarizes the in vivo IV pharmacokinetic study in rats and the collection of rat physiological parameters and in vitro ADME parameters. Chapter Six presents the construction and validation of the rat PermQ model and an application for evaluating the glycocalyx partitioning hypothesis. Chapter Seven details the future directions.
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