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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Determining Critical Physiological and Drug Specific Parameters for Enhancing a Physiologically Based
An Le1,2, Riyazuddin Mohammed2,3, Junmei Zhang2,3
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Pharmaceutics
|July 28, 2026
Summary
This study quantifies drug solubility, binding, and permeability in the female reproductive tract (FRT). Findings inform the development of safer, localized therapies for women's reproductive health by improving physiologically based pharmacokinetic (PBPK) models.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Women's Reproductive Health
- Biopharmaceutical Sciences
Background:
- Direct drug delivery to the female reproductive tract (FRT) offers targeted therapy with reduced systemic exposure for women's health.
- Limited quantitative data on solubility, binding, and permeability hinders the development of physiologically based pharmacokinetic (PBPK) models for FRT therapies.
- Understanding these parameters is crucial for designing effective intravaginal and intrauterine drug delivery systems.
Purpose of the Study:
- To quantify matrix-specific solubility, binding, and permeability of model drugs across human FRT tissues.
- To generate essential data for developing accurate PBPK models for localized FRT drug delivery.
- To inform the design of novel and improved women's reproductive health therapies.
Main Methods:
- Evaluated four model drugs (dapivirine, levonorgestrel, MK-2048, EFdA) using in vitro and ex vivo human FRT models.
- Quantified plasma solubility, matrix-specific binding (plasma, cervicovaginal fluid, tissues), and bidirectional permeability.
- Assessed drug transport characteristics, including efflux transporter involvement in Caco-2 and 3D vaginal models.
Main Results:
- Drug solubility varied with lipophilicity; plasma protein binding significantly enhanced solubility for all drugs.
- Matrix-specific binding strongly correlated with lipophilicity, with dapivirine showing the highest (97-99%) and EFdA the least (15-62%).
- FRT tissues exhibited distinct regional permeability patterns influenced by drug lipophilicity, ionization, and transporter activity.
Conclusions:
- Solubility, matrix-specific binding, and tissue permeability are key factors influencing drug distribution within the FRT.
- Experimentally derived parameters provide critical inputs for FRT PBPK model development.
- This research supports the creation of safer and more effective localized therapies for women's reproductive health.
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